Targeting Nuclear Receptors in Neurodegeneration and Neuroinflammation
- Sabine WillemsSabine WillemsInstitute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt, GermanyMore by Sabine Willems,
- Daniel ZaienneDaniel ZaienneInstitute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt, GermanyMore by Daniel Zaienne, and
- Daniel Merk*Daniel Merk*Email: [email protected]Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt, GermanyMore by Daniel Merk
Copyright © 2021 The Authors. Published by American Chemical Society
Abstract
Nuclear receptors, also known as ligand-activated transcription factors, regulate gene expression upon ligand signals and present as attractive therapeutic targets especially in chronic diseases. Despite the therapeutic relevance of some nuclear receptors in various pathologies, their potential in neurodegeneration and neuroinflammation is insufficiently established. This perspective gathers preclinical and clinical data for a potential role of individual nuclear receptors as future targets in Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, and concomitantly evaluates the level of medicinal chemistry targeting these proteins. Considerable evidence suggests the high promise of ligand-activated transcription factors to counteract neurodegenerative diseases with a particularly high potential of several orphan nuclear receptors. However, potent tools are lacking for orphan receptors, and limited central nervous system exposure or insufficient selectivity also compromises the suitability of well-studied nuclear receptor ligands for functional studies. Medicinal chemistry efforts are needed to develop dedicated high-quality tool compounds for the therapeutic validation of nuclear receptors in neurodegenerative pathologies.
1. Introduction
ARTICLE SECTIONS
Diseases associated with a loss of neuronal function such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) have a high and constantly growing global prevalence.(1,2) They span a wide spectrum of diseases leading to cognitive decline and/or disability affecting more than 40 million people in the world.(1,2) Neurodegenerative diseases are severe health burdens that massively affect quality of life and globally pressure healthcare systems and economics. In contrast to several other severe pathologies such as cancer or chronic inflammation, for which pharmacological treatment has significantly improved in the recent past, most neurodegenerative diseases lack efficient therapeutic interventions. The multifaceted neurodegenerative pathologies arise from different etiologies and disease mechanisms but still share certain common characteristics such as neuronal degeneration, loss of neuronal function, involvement of neuroinflammation, and in many cases the abnormal neuronal disposal of certain proteins.
Dementia including AD has a global prevalence of 5–7% in people above the age of 60 years(1,3) with 36 million patients in 2010 and an alarming estimated number of 115 million patients in 2050.(1) Despite these enormous numbers, current options for dementia treatment are almost negligible. For example, acetylcholinesterase inhibitors and memantine show only limited symptomatic effects(4,5) in early disease stages, and efficacy of ginkgo biloba could not be demonstrated, yet.(6) So far, no therapeutic intervention is available which counteracts underlying disease mechanisms.(7) Tau directed agents are immature,(8) and amyloid-β (Aβ) targeting therapies have failed in clinical development.(9) As a consequence of several recent drawbacks, research on pharmacological agents for dementia treatment has significantly decreased.(10) Improved understanding of the complex underlying pathomechanisms(11) and the search for new molecular targets to counteract AD and other forms of dementia are hence imperative. Therein, particularly regenerative strategies are urgently needed.(10)
PD, which mainly arises from degeneration of dopaminergic neurons in the substantia nigra due to deposition of α-synuclein and other toxic factors,(12) has an estimated prevalence of 1.0% in people above the age of 60.(13) Its pathology and disease mechanisms are better defined than in AD, and therapeutic options, which include, for example, dopaminergic agents, monoamine oxidase inhibitors, catechol-O-methyl transferase inhibitors, NMDA antagonists, and anticholinergics,(14) are somewhat more effective. Still, available therapeutic interventions for PD only address disease symptoms without affecting the underlying causes as well, and research on disease-modifying interventions that delay progression or even provide a cure was characterized by several recent failures, too.(15) Hence, new strategies to reverse the disease are urgently needed in PD.
MS is the most prevalent disabling disease in younger people and affects approximately 3 million people in the world.(16) An autoimmune destruction of neuronal myelin sheaths and constant neuroinflammation are the central factors in MS leading to progressive neuronal damage. The treatment of MS has markedly evolved over the last decades(17) allowing a significantly slowed progression with modern therapeutic interventions in several cases.(16,17) However, the multiple available MS treatment options target the immune system to counteract inflammatory processes and consequently prevent neuronal destruction.(18) Despite the remarkable progress achieved by the new MS medications, therapeutic interventions to reverse MS are urgently required.(18)
Several lines of evidence present certain nuclear receptors as potential molecular targets to treat neurodegenerative diseases. As ligand-sensing transcriptional regulators, nuclear receptors control metabolic homeostasis and have multiple cell-protective functions against toxic metabolites. Hence, a potential neuroprotective role of these transcription factors is obvious. Moreover, nuclear receptors are involved in the control of cell proliferation, differentiation, and survival, suggesting their modulation also as potential avenue to regenerative approaches. Putative strategies for regenerative treatment in neurodegenerative diseases may target neuronal protection and repair mechanisms. Therapeutic strategies which are able to promote neuronal regeneration, restore neuronal integrity, and counteract neuroinflammation would hold enormous potential for numerous diseases associated with neurodegeneration. Although the adult human brain is one of the organs with the lowest regenerative ability, neurogenesis occurs throughout life from neural stem cells (NSCs),(19) and knockout studies have already revealed certain growth factors and their downstream signaling pathways, transcriptional regulators, and epigenetic proteins as important mediators in neuroregeneration.(19) Putative novel therapeutic approaches to neurodegenerative diseases might target these regulatory proteins to modulate survival, proliferation, differentiation, or migration of NSCs. In addition to NSCs, which may open a general avenue to regenerative effects, other neuronal cell types hold regenerative potential in the various pathologies. Oligodendrocytes (OLs), for example, play a key role in myelination, and considerable efforts have been spent on identifying mechanisms that promote remyelination by OLs in MS.(18) This perspective gathers preclinical and clinical evidence for the potential of nuclear receptors(20) as future molecular targets in the treatment of neurodegenerative pathologies and focuses on the current stage of medicinal chemistry to target these transcriptional regulators as new avenues for a cure in neurodegenerative diseases.
2. Nuclear Receptors and Neurodegeneration
ARTICLE SECTIONS
The protein family of nuclear receptors (NRs) in humans comprises 48 members (Figure 1a) that act as ligand-sensing transcription factors and regulate gene expression profiles upon changes in ligand concentrations.(21) As their key function, NRs translate stimuli by signal molecules—e.g., hormones or lipid mediators—into enhanced or decreased expression of certain sets of genes. However, the cellular functions of NRs are multifaceted (Figure 1b,c) and include direct and indirect genomic effects, for example, by interacting with other transcription factors (tethering, transrepression, Figure 1c), as well as nongenomic activities. The complex roles and network of NRs involve multiple regulatory mechanisms (reviewed in, e.g., refs (22−25)) such as ligand-dependent and -independent regulation, post-translational modifications (phosphorylation and SUMOylation) which can be activating or inhibiting, ligand effects on subcellular localization, NR monomer–dimer–oligomer equilibria, and a network of coregulators that are recruited or released upon ligand binding.(26) Most NRs share a typical common architecture of an N-terminal ligand-independent activation function 1 (AF-1) followed by the DNA binding domain (DBD) and a C-terminal ligand binding domain (LBD), the latter of which recognizes the ligand and undergoes conformational changes upon ligand binding.(27,28) These changes often affect the structure and position of the so-called ligand-dependent activation function 2 (AF-2), which is located in the C-terminal helix (H12) of the LBD. Ligand chemotype recognition varies remarkably between different NRs, enabling selective NR modulation by small molecule ligands and rendering NRs as attractive targets for a pharmacological modulation of gene expression.(21,26) About half of the NR family is well studied and has pharmacological relevance. Endogenous ligands of these receptors are known, and several potent and selective small molecule modulators are available to determine their roles in health and disease. For other NRs, available knowledge on ligands, biochemical function, and interaction networks as well as pathological relevance is limited, and for several so-called orphan NRs,(29) endogenous ligands remain elusive. Some nuclear receptors are considered as potentially attractive pharmacological targets in the context of neurodegeneration based on varying levels of evidence. In the following, we summarize findings pointing to an involvement of individual NRs in neurodegeneration, neuroprotection, and neuroinflammation, and discuss the potential and limitations of their available ligands.
Figure 1
Figure 1. Nuclear receptors. (a) Overview over the nuclear receptor superfamily comprising 48 members in human.(30) (b) Basic mechanism of genomic nuclear receptor function. NRs of the NR1 family like LXRs and PPARs bind to their specific NRE within the promoter region of their target genes as obligate heterodimers with RXR. In the absence of ligand binding, these heterodimers associate with corepressor complexes, which results in repression of transcription. Conformational changes of the complex occur upon ligand binding, which involves displacement of the corepressor complex and subsequent coactivator recruitment, resulting in the transcription of target genes. (c) Exemplified indirect genomic action of nuclear receptors. For example, NFκB-regulated pro-inflammatory genes are differently controlled by NRs. Monomers such as PPARγ or LXR can undergo SUMOylation upon ligand binding and recruit corepressors to inhibit gene expression via NFκB (p50 and p65 subunits) interaction with its response elements.
2.1. Peroxisome Proliferator-Activated Receptors (PPAR, NR1C)
2.1.1. Overview
The three peroxisome proliferator-activated receptors PPARα, PPARγ, and PPARδ (also termed PPARβ) are cellular lipid sensors and considered as master regulators of lipid and glucose homeostasis.(31) While the PPARs are differentially expressed in peripheral tissues with PPARα as the major hepatic isoform, PPARγ in adipose tissue and immune cells, and ubiquitous expression of PPARδ, all three subtypes are found in the brain with the highest levels in neurons.(32) PPARs are activated by various nutritional and endogenous lipids such as polyunsaturated fatty acids, vitamin E metabolites, and fatty acid mimetic molecules.(31,33−35) The PPARα and PPARγ isoforms have a long history as drug targets in metabolic diseases (PPARα: hyperlipidemia, PPARγ: type 2 diabetes), but relevance of fibrates (PPARα agonists), glitazones (PPARγ agonists) and glitazars (dual PPARα/γ agonists) for these indications has declined.(31,36) Preclinical evidence ascribes all three PPARs therapeutic potential in a number of neurodegenerative pathologies, and interest of drug discovery and pharmacology in the PPARs remains high.
2.1.2. PPARs in Alzheimer’s Disease
In AD, evidence for therapeutic potential is mainly available for PPARγ activation. Observational studies in patients receiving antidiabetic medication point to a protective role of PPARγ activation.(37−39) In several large cohorts, treatment with the PPARγ agonist pioglitazone (1) decreased the risk of developing dementia.(37−39) Additionally, some nonsteroidal anti-inflammatory drugs (NSAIDs) were found to reduce the risk for AD, which might be associated with the PPARγ agonistic component of these drugs.(2,40) The therapeutic potential of PPAR activation in AD-related pathologies is rationalized by PPAR-mediated reduction of Aβ and tau burden, anti-inflammatory activities, and protective effects on mitochondria.(2,41) Numerous preclinical studies have observed beneficial effects in AD-related models. For example, PPARγ activation caused upregulation of insulin-degrading enzyme in primary neurons from rats and AD model mice, a protease which is also able to degrade Aβ.(42,43) Additionally, PPARγ activity was found to decrease expression of β-secretase, which cleaves amyloid precursor protein (APP) to produce Aβ.(43−45) PPARγ activation with pioglitazone (1) in rats,(46) in double transgenic APP/PS1 mice,(47) and in triple transgenic AD mice(48) reduced Aβ levels in the central nervous system (CNS) and improved energy homeostasis, whereas the irreversible PPARγ antagonist GW9662 (2) caused the opposite effect.(49) Congruently, several studies(50,51) report reduced memory deficits in APP/PS1 mice upon pioglitazone (1) treatment, while intraventricular administration of the PPARγ antagonist GW9662 (2) caused motor dysfunction.(49) In APP/PS1 mice, pioglitazone (1) was also remarkably effective in clearing Aβ, decreasing neuroinflammation, and improving cognitive function when administered in a short-term fashion after disease onset.(52) Similar improvements of cognitive deficits upon pioglitazone (1) treatment were observed in double transgenic mice expressing mutant human APP and a constitutively active form of transforming growth factor-β1 (TGF-β1) but without effects on Aβ burden.(53) In rats receiving an intracerebroventricular Aβ injection to establish an AD model, pioglitazone (1) improved cognitive function, reduced neuroinflammation, and reversed oxidative mitochondrial damage.(54) PPARγ antagonist treatment counteracted the beneficial effects of pioglitazone (1). Pioglitazone (1) was also found to improve synaptic function in APP/PS1 mice in a pathway involving cyclin-dependent kinase 5 (cdk5).(51) Moreover, pioglitazone (1) and troglitazone reduced tau protein levels and tau aggregation in cellular models and in primary neurons, while GW9662 (2) reversed these effects.(55,56) Accordingly, four months of treatment with pioglitazone (1) and rosiglitazone (3) attenuated tau hyperphosphorylation in triple transgenic AD mice.(48)
Despite the mostly promising preclinical observations, late-stage clinical trials with the PPARγ agonist rosiglitazone (3) failed to reveal a clinical benefit in the treatment of mild-to-moderate AD.(57,58) Meta-analyses of the reported small and larger clinical trials on pioglitazone (1) and rosiglitazone (3) in AD came to the conclusion that based on the available data rosiglitazone (3) has no benefit in mild-to-moderate AD, while pioglitazone (1) might have some efficacy.(59,60)
2.1.3. PPARs in Parkinson’s Disease
Protective effects of PPAR activation in PD have also been reported from numerous preclinical models with a focus on the PPARγ agonistic thiazolidinediones. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, pioglitazone (1) prevented microglial activation and loss of dopaminergic neurons,(61) restored tyrosine hydroxylase (TH) levels,(61) and improved motor impairments.(62) A potential involvement of monoamine oxidase B inhibition(62) in these effects of pioglitazone (1) is speculated. Rosiglitazone (3) exhibited anti-inflammatory effects in MPTP-induced PD in mice, too, and reverted microglial activation as well as pro-inflammatory cytokine levels.(63) Pioglitazone (1) was even examined in MPTP-induced PD in rhesus monkeys, where it also normalized TH levels and other CNS markers of PD. Concomitantly, pioglitazone (1) administration (5 mg/kg p.o. daily) caused a marked improvement in several behavioral tests compared to placebo-treated animals including performance in fine motor skills.(64) Even in a rare and severe model of late-stage PD in mice induced by mitochondrial complex IV defects in dopaminergic neurons, which is characterized by extensive loss of dopaminergic neurons and strong motor deficits, pioglitazone (1) exhibited improvements in motor impairment and neuroinflammation.(65)
In addition to the glitazones, neuroprotective and anti-neuroinflammatory effects in the rodent MPTP model were also observed upon treatment with the non-thiazolidinedione PPARγ (partial) agonists MDG548(66,67) or LSN862,(68) which further corroborates involvement of PPARγ modulation in therapeutic effects. Moreover, treatment of lipopolysaccharide (LPS)-stimulated primary mouse microglia with MDG548 revealed increased phagocytic activity as another potential mechanism of PPAR-mediated beneficial effects in neurodegenerative diseases.(67)
Similar to PPARγ agonists, the PPARα agonist fenofibrate, the structurally related PPARδ agonists GW0742 (4) and GW501516 (5), and the dual PPARα/γ agonist MHY908 ameliorated MPTP-induced PD in mice with cognitive and locomotor improvements, reduced TH levels, decreased neuroinflammation, and less neuronal damage in several studies.(69−74) In line with this, PPARδ antagonist (GSK0660) treatment worsened the toxicity of 1-methyl-4-phenylpyridinium iodide (MPP+) on neuronal cells in vitro, while the agonist GW0742 (4) reversed this effect.(72) Neuron-specific knockout of PPARγ and/or PPARδ in the MPTP-induced model of PD did, however, not result in more severe neuronal damage, potentially suggesting that PPAR in other cell types is important for the protective effects observed with PPAR agonists.(75) In the less common rotenone-induced rat model of PD, which has a strong endoplasmic reticulum stress component, intracerebroventricular infusion of PPARδ agonist GW501516 (5) improved locomotor activity, decreased endoplasmic reticulum stress, reduced neuronal apoptosis, and counteracted the loss of dopaminergic neurons.(76)
PPAR ligands were also examined in the 6-hydroxy dopamine (6-OHDA)-induced rodent model of PD. Pioglitazone (1) decreased mortality, ameliorated microglial activation and reduced NFκB activity, enhanced neuronal survival, and improved locomotor deficits in 6-OHDA treated rats.(77,78) Similarly, intraperitoneal administration of rosiglitazone (3) to 6-OHDA rats restored TH levels, prevented microglial activation, and decreased pro-inflammatory markers such as cyclooxygenase-2 (COX-2) and tumor necrosis factor α (TNFα) in the CNS.(79) Since the beneficial effects of rosiglitazone (3) were strengthened when the drug was administered before disease induction, a potential involvement of decreased COX-2 activity in the neuroprotective effects is speculated.(79) In an extended 6-OHDA rat model with concomitant chronic levodopa administration, rosiglitazone (3) was also found to attenuate levodopa-induced dyskinesia.(80)
A recent in vitro study provided a link between PPARs and Nurr1 (see section 2.7.2) activity.(81) A PPAR response element is located in the promoter region of the neuroprotective transcription factor Nurr1, and the PPARα agonist gemfibrozil enhanced Nurr1 expression in wild-type but not in PPARα knockout dopaminergic neurons and mice.
In line with the promising neuroprotective activities of PPARγ agonists in preclinical models of PD, a retrospective study has revealed protective effects of glitazone(82) intake. Incidence of PD was reduced in patients receiving a thiazolidinedione as antidiabetic medication compared to other antidiabetic drugs. Previous thiazolidinedione use was not protective,(82) and no protective effect was observed for fibrate use.(83)
2.1.4. PPARs in Multiple Sclerosis
In MS patients, a significant upregulation of PPARγ has been detected in cerebrospinal fluid (CSF).(84) PPARγ levels additionally correlated with the number of immune cells and IgG index in CSF as neuroinflammatory markers.(84) PPARα, PPARδ, and the key PPAR coactivator PGC-1α were below the detection limit and hence not considered as elevated.(85) A recent study(86) reported strong downregulation of PPARγ but not PPARα or LXRα/β in macrophages derived from MS patients compared to healthy controls. Moreover, treatment of macrophages from healthy donors with the MS-associated pro-inflammatory cytokines interferon γ (IFNγ) and interleukin-1 β (IL-1β) resulted in a similar downregulation of PPARγ.
In line with these findings, considerable preclinical evidence for the therapeutic potential of PPAR agonism in MS has accumulated and mainly suggests the PPARγ subtype as a promising target. Multiple studies have demonstrated that PPARγ activation by pioglitazone (1)(87−89) or 15-deoxy-delta(12,14)-prostaglandin J(2) (15d-PGJ2)(90) treatment ameliorates experimental autoimmune encephalomyelitis (EAE), and, expectedly, dual treatment with 15d-PGJ2 and RXR agonist 9-cis retinoid acid (9-cis RA, 43) achieved enhanced efficacy.(91) Mechanistically, these effects of PPARγ activation are hypothesized to involve protective effects on mitochondria, enhanced OL differentiation, anti-inflammatory effects on phagocytic macrophages and microglia, and modulation of T cell differentiation.
In cellular setting, pioglitazone (1) or docosahexaenoic acid (45) activated PPARγ in oligodendrocyte progenitor cells (OPCs) to promote their maturation. The effect was blocked by the PPARγ antagonist GW9662 (2). PPARγ activation also counteracted the TNFα-induced arrest of OPCs in a pathway putatively involving phosphorylation of extracellular signal kinases (ERKs).(92) Moreover, PPARγ agonists were found to protect OLs against inflammatory damage to mitochondria.(93) Inflammatory stimuli with TNFα cause enhanced superoxide production by mitochondria and decreased membrane potential. Pioglitazone (1) counteracted these effects and promoted PGC-1α expression, which increases the biogenesis of mitochondria.
Treatment of primary mouse microglia with PPARγ agonists (15d-PGJ2, pioglitazone (1), rosiglitazone (3), ciglitazone) prevented LPS- or cytokine-induced NO production, IL-1β release, and IL-6 release.(94) Similar effects were observed in primary mouse astrocyte cultures(94) and in primary rat Schwann cells.(95) A recent study demonstrated the importance of the PPARγ-regulated fatty acid translocase CD36 in clearance of myelin debris by phagocytes and suppression of neuroinflammation.(96) Through enhanced CD36-mediated myelin uptake, phagocytic macrophages and microglia adopted a less inflammatory phenotype. Inhibition of CD36 promoted neuroinflammation in EAE. In line with this, Wouters et al.(86) detected increased PPARγ signaling in macrophages upon myelin phagocytosis—potentially induced by fatty acids contained in myelin debris—which was blocked by GW9662 (2). PPARγ expression was not altered by myelin uptake. Vice versa, the PPARγ antagonist GW9662 (2) did not affect myelin phagocytosis but disturbed intracellular lipid processing.
In T cells, PPARγ activation was found to act as a negative regulator of differentiation to Th17 cells in a pathway involving TGF-β, IL-6, and RORγt.(88) The PPARγ agonists pioglitazone (1), ciglitazone, and GW347845 reduced proliferation and pro-inflammatory cytokine secretion in a T cell line (Jurkat) and in phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) derived from 21 MS patients and 12 healthy donors.(97) In EAE, pioglitazone (1) treatment selectively reduced Th17 but not Th1 differentiation.(88) Th17 cell differentiation was also reduced by treatment with an endogenous PPARγ activator (13s-HODE).(88) T cell-specific PPARγ knockout had the opposite effect, strongly enhanced Th17 cell differentiation, and caused an earlier disease onset in EAE.(88) Notably, pioglitazone (1) treatment of T cells from healthy donors or MS patients also reduced the number of IL-17 producing T cells formed upon TGF-β/IL-21 stimulation.(88) PPARγ is hence speculated to regulate autoimmunity in the CNS by controlling T cell differentiation.(88)
Some studies also point to a potential of PPARδ in MS. Treatment with the PPARδ agonist GW0742 (4)(98) had therapeutic efficacy in EAE, and PPARδ-deficient mice displayed prolonged disease duration in EAE with compromised remission and recovery.(99) Therein, PPARδ knockout animals revealed elevated INFγ and IL-17 levels in the brain and alterations in T cell populations. In an in vitro model of demyelination and neuroinflammation using embryonal rat neuronal cells and antibodies against myelin oligodendrocyte glycoprotein (MOG), PPARδ agonist GW501516 (5) exhibited anti-inflammatory effects but failed to counteract demyelination-induced changes in gene expression.(100) In MOGp35-55-induced EAE in mice, PPARδ activation (with GW501516 (5) or L165041 (6)) counteracted IFNγ and IL-17 production by T cells and lowered levels of other pro-inflammatory cytokines in the CNS.(101) PPARδ activation is therefore speculated to have anti-inflammatory effects in MS and might be involved in remission and recovery of MS-associated pathology. In line with this, treatment of human OLs or primary mouse OLs with the nonselective PPAR agonist gemfibrozil promoted differentiation and enhanced expression of myelin-related genes.(102,103) In primary mouse OLs, the effect was lost in cultures from PPARδ-deficient animals but not in cells lacking PPARα.(102)
On the basis of accumulating evidence for the therapeutic potential of PPARγ activation in MS, pioglitazone (1) was studied in some small clinical trials. In a one-year, placebo-controlled trial, pioglitazone (1) use was safe in relapsing remitting MS.(104) The study discovered a reduction in gray matter atrophy and a tendency to decreased lesion burden, while no improvement in the expanded disability status scale was observed.(104) Another small study suggested that pioglitazone (1) treatment may reduce lesion development in relapsing remitting MS.(105) In a cohort study(106) with MS patients also affected by the metabolic syndrome, treatment with either of the antidiabetic drugs metformin and pioglitazone (1) over 6 months resulted in a decreased number of lesions compared to untreated patients. Both drugs also had anti-inflammatory effects as observed by lower cytokine secretion. This limited evidence for therapeutic efficacy of pioglitazone (1) in MS is encouraging, but larger and longer trials would be needed to demonstrate a clinical benefit. Moreover, it may be doubted whether poorly CNS available pioglitazone (1) is a good choice in this indication since PPARγ activation in the brain appears to mediate the desired anti-inflammatory and neuroprotective effects.
2.1.5. PPAR Ligands
In the past, the PPARs have been in the focus of drug discovery for their involvement in metabolic balance and their potential as drug targets for highly prevalent metabolic diseases.(36) Extensive efforts were made to develop various types of PPAR ligands (Scheme 1). Numerous subtype selective and nonselective ligands target one, two, or all three PPARs. Elafibranor (7)(107) activates PPARα and PPARδ, farglitazar (8)(108−110) is an example of a potent dual PPARα/γ agonist, L796449 (9)(111) is a dual PPARγ/δ agonist, and GW9578 (10)(112) is a balanced pan-PPAR agonist. Achieving subtype selectivity among the PPARs is not trivial, but several potent subtype selective agonists have been developed. GW7647 (11),(112) CP-775146 (12),(113) and NS-220 (13, also termed LS-191458)(114) are potent and selective PPARα agonists. In past studies, Wy-14643 (14)(115) was used as PPARα agonist but later found to activate PPARγ(116) and RXRs(117) as well. For PPARγ, the drug approved thiazolidinediones rosiglitazone (3)(118) and pioglitazone (1),(119) GW1929 (15),(120) and 16(121) comprise high potency and strong subtype selectivity. In addition, the covalent, irreversible PPARγ antagonist GW9662 (2)(122) is a very valuable tool to study PPARγ biology. L165041 (6),(111) GW501516 (5),(123,124) GW0742 (4),(124) and seladelpar (17)(125) are the most selective PPARδ activators with high potency. Since the majority of PPAR agonists comprise acidic, fatty acid mimetic structures,(34) their CNS availability is limited, however. Several preclinical studies have hence applied the PPAR agonists via intracerebroventricular infusion.(74) Pioglitazone (1), the most widely used PPARγ agonist in studies and trials on neurodegenerative diseases, presents poor CNS availability mainly due to P-glycoprotein (P-gp) efflux.(126) GSK1997132B (18)(127) has been specifically developed as a brain-penetrant (partial) PPARγ agonist.
Scheme 1
Scheme 1. Selected PPAR Ligands Used in Studies on Neurodegeneration or with Preferable Tool Compound Characteristics
2.1.6. Conclusion
Overall, activation of PPAR, especially the PPARγ subtype, has been found to exhibit attractive effects in multiple in vitro and in vivo models of neurodegenerative diseases (summarized in Table 1), but translation toward therapeutic efficacy in humans is lacking. This may be due to a merely protective rather than therapeutic role of PPAR agonism, which aligns with observations that the use of pioglitazone (1) as an antidiabetic medication reduced AD risk and PD incidence. It may also be speculated that the glitazones, which were used in the majority of preclinical studies on neurodegeneration but have poor CNS bioavailability, exhibited most of their effects through peripheral rather than CNS activity. PPAR ligands specifically designed for blood–brain barrier (BBB) penetration are needed to further validate PPAR activation as a therapeutic approach in neurodegeneration. Additionally, the beneficial effects observed with glitazones require confirmation with other PPAR agonist scaffolds to exclude involvement of other, non-PPAR-mediated mechanisms.
Table 1. Summarized Observations on PPARs in Neurodegeneration
| PPARα (= NR1C1), PPARδ (= NR1C2; also known as PPARβ, NUC1, and FAAR), and PPARγ (= NR1C3) | |
|---|---|
| PPARs in AD | Pioglitazone (1) use reduced AD risk in cohort studies.(37−39) |
| PPARγ activation induces insulin-degrading enzyme which can degrade Aβ.(42,43) | |
| PPARγ activation downregulates β-secretase which cleaves APP to produce Aβ.(43−45) | |
| PPARγ activation decreased memory deficits(50,51) and reduced Aβ(46−48) and tau(48) levels in rodent models of AD. | |
| PPARs in PD | PPAR activation prevented microglial activation and loss of dopaminergic neurons, restored tyrosine hydroxylase (TH) levels, and improved motor impairments in rodent models of PD (PPARα,(69−74) PPARγ,(61−65,77−80) PPARδ(69−74)). |
| Incidence of PD was reduced in patients receiving pioglitazone (1) as an antidiabetic medication.(82) Fibrate use had no such effect.(83) | |
| PPARs in MS | PPARγ but not PPARα and PPARδ was found upregulated in CSF of MS patients.(84,85) |
| PPARγ but not PPARα and LXR was found downregulated in macrophages from MS patients.(86) | |
| PPARγ activation ameliorated EAE.(87−90) | |
| PPARδ activation ameliorated EAE,(98) and PPARδ knockout compromised recovery from EAE.(99) | |
| PPARγ activation reduced inflammatory response of PBMCs from healthy donors and MS patients.(97) | |
| PPARγ activation prevented arrest of OPCs(92) and protected OLs against inflammatory damage.(93) | |
| PPARγ activation induced CD36 to enhance myelin debris clearance.(96) | |
| Pioglitazone (1) treatment reduced number of lesions and gray matter atrophy in MS patients.(104−106) | |
2.2. RevERB (NR1D)
2.2.1. Overview
Recent data also point to a potential involvement of the transcriptional repressors reverse ERB (revERBα, NR1D1; revERBβ, NR1D2) in neurodegenerative pathologies.(128,129) These proteins participate in the circadian clock as repressors and are considered as counterparts/antagonists of the retinoic acid receptor related orphan receptors (RORs).(129,130) RevERBα is encoded by the opposite DNA strand of the thyroid hormone receptor α (THRα, also termed ERBA oncogene) explaining the unusual name of the nuclear receptor.(129,131) RevERBs act mainly as monomers and lack the typical C-terminal AF-2 of NRs providing a first hint to their transcriptional repressor activity.(132,133) Accordingly, revERBs strongly recruit corepressors such as NCoR, resulting in chromatin condensation and gene repression.(134) Expression of revERBs varies in a circadian fashion.(135,136)
2.2.2. RevERB in Neuroinflammation
A number of preclinical studies have revealed promising effects of revERB modulation in neuroinflammation and neurodegeneration, but the reported observations are also controversial. In vitro, effects of treatment with the revERB agonist SR9011 (19) were analyzed in primary microglia from neonatal rats.(137) The compound diminished pro-inflammatory cytokine release upon TNFα treatment and decreased phagocytic activity. Mitochondrial activity and ATP generation as well as expression of genes involved in carbohydrate metabolism were also reduced. Guo et al.(138) found beneficial effects of pharmacological revERBα activation with GSK4112 (20) and SR9011 (19), which dose-dependently counteracted LPS-induced microglial activation in the murine microglial cell line BV2, in primary mouse microglia, and in mice. The observed anti-inflammatory effects of revERBα activation involved NFκB-dependent pathways and a decreased release of pro-inflammatory cytokines.
2.2.3. RevERB in Alzheimer’s Disease
Similarly, the revERB activator SR9009 (21) counteracted cognitive dysfunction and decreased cortical Aβ levels in the SAMP8 mouse model of AD.(139) Additionally, revERB activation enhanced the number of synapses and upregulated marker proteins of synaptic health, which are decreased in the disease model. In line with these findings, Griffin et al.(140) showed that revERBα knockout enhanced microglial activation in vivo with spontaneous inflammation in the hippocampus, and revERBα knockout mice revealed a markedly increased neuroinflammatory reaction to LPS. As in other studies, these effects were linked to altered NFκB signaling. In vitro, cultured revERBα-deficient primary microglia exhibited a pro-inflammatory phenotype, and a coculture model revealed increased neuronal death for revERBα-deficient microglia. Somewhat contradictory to these encouraging observations for pharmacological revERB activation, Lee et al.(141) discovered beneficial effects in neurodegeneration upon inhibition of revERB activity. RevERB knockdown or inhibition with the antagonist SR8278 (22) in the 5XFAD model of AD in mice enhanced Aβ uptake by microglial cells and decreased size and number of Aβ plaques.
2.2.4. RevERB in Multiple Sclerosis
Chang et al.(130) probed the role of revERB in EAE and observed anti-inflammatory activity of the transcription factor in Th17 cells. RevERB antagonized RORγt, which regulates expression of IL-17 to drive inflammation. RevERB overexpression or treatment with revERB activator SR9009 (21) remarkably ameliorated EAE in mice and suppressed disease progression. At the same time, Chang et al. also observed milder EAE in revERB-deficient mice, however, which appeared to be due to disturbed T cell differentiation to Th17 cells. Hence, despite being promising, the findings on revERB modulation in neurodegenerative and neuroinflammatory pathologies are inconsistent.
2.2.5. RevERB Ligands
In the recent decade, considerable knowledge on revERB ligands has been obtained (summarized in a recent review(128)). Heme was found as a natural revERB ligand(142) and constitutes the first endogenous nuclear receptor ligand which is not a hormone, steroid, or lipid. Medicinal chemistry has provided a number of revERB modulators as useful tool compounds (Scheme 2). GSK4112 (20) is the prototype of the most widely used revERB agonists, and several descendants (19, 21–26) of this chemotype with enhanced potency and improved properties were developed.(128,129) Within this series, GSK2945 (23) provides the most preferable profile with high revERB agonist activity (EC50 0.05 μM), sufficient selectivity, and a pharmacokinetic profile suitable for in vivo studies.(143) In addition, two further revERB agonist chemotypes have been described,(144,145) exemplified by 27 and 28, which are highly active examples of each series with sub-micromolar potencies. Development of revERB antagonists was not as successful as for agonists. SR8278 (22) with an IC50 value of 0.47 μM is the most potent tool to date.(128,129,146) Two further weak revERB antagonist scaffolds (29, 30)(147,148) have been recently described and provide a solid basis for the development of improved tools to study revERB biology.
Scheme 2
Scheme 2. RevERB Modulators
2.2.6. Conclusion
Despite some promising observations (summarized in Table 2), available data on revERB in neurodegeneration are limited and contradictory since beneficial effects were observed for both knockout/inhibition and overexpression/activation. Consistent understanding of the transcription factor’s role in neurodegeneration is lacking, and further research is required to validate revERB as a therapeutic target. Additional and improved tool compounds to study pharmacological revERB modulation will be needed since the revERB activators GSK4112 (20), SR9009 (21), and SR9011 (19) that were used in most experiments share a common chemotype and are likely to share common off-targets. Accordingly, a recent report(149) suggests revERB-independent effects of SR9009 (21). Validation of revERB would strongly benefit from a set of structurally diverse modulator scaffolds to exclude off-target effects in a chemogenomic fashion. RevERB modulator development should also consider the CNS as attractive site of action and provide BBB penetration data. In addition, the majority of studies on revERB in neurodegeneration have been conducted without important control experiments such as revERB knockdown to validate revERB-mediated effects. Future studies would profit from considering the unclear specificity of revERB ligands and a design comprising control experiments to demonstrate involvement of revERB modulation in therapeutic effects.
Table 2. Summarized Observations on revERB in Neurodegeneration
| RevERBα (= NR1D1; also known as EAR1) and revERBβ (= NR1D2; also known as EAR1β, BD73, RVR, and HZF-2) | |
|---|---|
| RevERB in neuroinflammation | RevERBα knockout in mice enhanced microglial activation and neuroinflammatory reaction to LPS.(140) |
| RevERB activation counteracted microglial activation(138) and pro-inflammatory cytokine release.(137) | |
| RevERB in AD | RevERB knockout or inhibition enhanced microglial Aβ uptake and decreased the size and number of Aβ plaques in 5XFAD mice.(141) |
| RevERB activation decreased cognitive dysfunction and cortical Aβ levels in a rodent AD model.(139) | |
| RevERB in MS | RevERB knockout caused milder EAE.(130) |
| RevERB overexpression or activation ameliorated EAE and suppressed disease progression.(130) | |
2.3. Liver X receptors (LXRs)
2.3.1. Overview
The liver X receptors (LXRs)(150) act as key regulators of cholesterol homeostasis and as such control, for example, the expression of the cholesterol transporters ATP-binding cassette transporter A1 (ABCA1) and ABCG1 as well as the apolipoproteins ApoE and ApoC. Additionally, LXR activation exhibits anti-inflammatory effects. The receptors are endogenously activated by oxysterols (oxidized cholesterol derivatives) such as 24(S),25-epoxycholesterol and 24(S)-hydroxycholesterol, the latter of which is also found in the brain with high abundance and hence also termed cerebrosterol.(151,152) The two LXR subtypes (LXRα, NR1H2; LXRβ, NR1H3)(150) are structurally conserved but differ in their expression patterns. LXRα is found at high levels in liver, intestine, adipose tissue, and macrophages, while LXRβ is ubiquitously expressed. The therapeutic potential of LXR modulation in neurodegeneration is mainly attributed to three general mechanisms, the regulation of (CNS-)cholesterol homeostasis, anti-inflammatory effects, and involvement in Aβ elimination in AD.(152−155)
2.3.2. LXR, Cholesterol, and Neuronal Health
Approximately one-fourth of the body’s cholesterol content is found in the CNS where it is a key component of myelin sheaths and neuronal cell membranes illustrating the importance of cholesterol homeostasis in the brain.(156−158) Most of the CNS cholesterol content arises from de novo synthesis—mostly by astrocytes—which as cholesterol transport and degradation is tightly regulated by LXRs.(152,159) LXR agonists were found to promote the cholesterol supply from astrocytes to neurons via induction of the cholesterol transporters ABCA1 and ABCG1 mediating cholesterol efflux and via upregulation of ApoE for cholesterol transport to neurons.(159,160) LXR activity hence appears crucial for neuronal health, and several knockout studies support this hypothesis. While LXRα knockout mainly impairs peripheral cholesterol homeostasis,(161) LXRβ-deficient mice at seven months of age developed neuronal lipid accumulation, degeneration of motor neurons, and axonal atrophy resulting in an amyotrophic lateral sclerosis-like phenotype.(162,163) Double knockout of both LXR subtypes in mice led to impairment in spatial learning and motor coordination which was associated with thinner myelin sheaths in the cerebellum.(164) Expression levels of the myelin components myelin basic protein and proteolipid protein as well as ABCA1 were decreased in these animals.(164) Knockout of LXRβ also caused neurodegeneration of the optic nerve and in retinal ganglia, and was associated with increased deposition of Aβ in ganglion cells, while LXRα-deficient mice did not show such characteristics.(165)
2.3.3. LXR in Alzheimer’s Disease
Most efforts in studying LXRs in neurodegeneration focused on aspects of AD. Anti-inflammatory effects of LXR activation were found to be beneficial in several in vitro and in vivo studies related to AD. Both LXRs are found in microglial cells.(166) Treatment of primary microglia from wild-type mice with Aβ causes an inflammatory response with upregulation of, for example, RANTES, TNFα, IL-1β, COX-2, and inducible NO-synthase (iNOS). In primary mouse microglia, LXR agonist (T0901317 (31)) treatment diminished Aβ-stimulated expression of these pro-inflammatory genes including COX-2 and iNOS, and counteracted NFκB activation.(166,167) Primary microglia from LXR knockout mice displayed diminished ABCA1 expression but similar basal levels of pro-inflammatory genes. Upon Aβ treatment, however, the inflammatory response of LXR knockout microglia was stronger than for wild-type glia.(166) LXR activity, therefore, seems to counteract neuroinflammatory responses to Aβ.
In addition to LXR-mediated anti-inflammatory effects, a potential relevance of LXR in AD is rationalized by the observation that ApoE associates with Aβ plaques and that the ApoE epsilon-4 (ApoE-ϵ4) allele is strongly associated with an increased risk for AD.(168) With levels as high as 5% of extracellular soluble protein, ApoE is highly abundant in the brain.(168) It is secreted mainly by astrocytes and serves for cholesterol transport in the CNS.(168−170) Early in vitro and in vivo studies(171−173) on effects of LXR on ApoE, ABCA1, and Aβ levels have reported conflicting observations. While these studies agree that LXR activation causes ABCA1 upregulation, Fukumoto et al.(171) observed increased secretion of Aβ upon LXR activation, whereas later reports detected decreased cellular Aβ secretion(172) and production(173) upon LXR agonist (T0901317 (31)) treatment.
In transgenic APP23 mice with neuronal expression of a disease-associated APP, a high-fat/high-cholesterol diet was found to exacerbate the disease as observed by a higher Aβ load and impaired spatial learning and memory function. LXR agonist treatment (T0901317 (31)) counteracted these effects of a high-fat/high-cholesterol diet,(174) suggesting an involvement of lipid/cholesterol homeostasis in LXR-mediated effects on Aβ load and cognitive function.
LXR activation with T0901317 (31) in double transgenic APP/PS1 mice expressing human APP with disease-associated mutations and presenilin 1 (PS1) decreased membrane cholesterol levels in the CNS.(175) APP levels were not affected by LXR agonist treatment, but LXR activation reduced β-secretase expression and activity resulting in lower Aβ levels. A connection between membrane cholesterol levels and β-secretase activity was deduced from in vitro experiments in which membrane cholesterol depletion in primary mouse neuronal cells with β-methyl cyclodextrin reduced β-secretase activity. LXR agonist treatment diminished membrane cholesterol levels and β-secretase activity in primary mouse neuronal cells, as well, and this effect was abrogated by ABCA1 inhibition with glyburide. In contrast to these observations, silencing of LXRβ in primary rat neurons expectedly decreased expression of ABCA1 but also lowered cholesterol levels.(176) Concomitantly, HMG-CoA reductase expression and secretion of Aβ were reduced.
Genetic knockout of either LXR subtype in transgenic APP/PS1 mice increased Aβ plaque burden and plaque size with a stronger effect of LXRα knockout.(166) In line with this, treatment of LXR wild-type transgenic APP/PS1 mice with the LXR agonist T0901317 (31) decreased Aβ levels and deposition(167) and reduced microglial activation as well as pro-inflammatory cytokine levels in the CNS. Pharmacological LXR activation furthermore increased the number of cholinergic neurons in the transgenic animals compared to vehicle treatment and improved spatial learning as observed by a maze test. In a related in vivo study using double transgenic APP/PS1 mice, long-term pharmacological LXR activation with T0901317 (31) failed to reduce Aβ plaques but improved memory function in object recognition and object location tests.(177) In a triple transgenic mouse model of AD (3xTgAD, also involving Tau pathology), treatment with the LXR agonist GW3965 (32) increased expression of ABCA1 and ApoE in the CNS.(178) Interestingly, higher ApoE expression upon LXR agonist treatment was mainly found in neurons. Additionally, GW3965 (32) treatment enhanced expression of neural stem cell and proliferation markers. LXR agonist-treated transgenic mice demonstrated significantly improved performance in learning tasks compared to vehicle-treated animals. No effects of LXR agonist treatment on Aβ load were detected, however. These results suggest other mechanisms of LXR activation mediating cognitive improvements in AD. A recent in vitro study(179) on hippocampal neurons suggested that oligomeric Aβ alters expression levels of synaptic proteins and the number of synaptic contacts. Treatment with the LXR agonist GW3965 (32) prevented synaptic changes, increased the expression of neuronal survival genes, decreased caspase activity, and promoted the number of synaptic contacts. The not fully consistent effects of T0901317 (31) and GW3965 (32) in AD-related studies might at least partly arise from different selectivity profiles since T0901317 (31) also modulates RORs.(180)
2.3.4. LXR and Parkinson’s Disease
While the therapeutic potential of LXR modulation in AD has been extensively evaluated, few studies have focused on LXR in PD, but there are observations supporting a role of LXR also in this pathology. In addition to the general anti-neuroinflammatory effects of LXR (2.3.2), the MPTP-induced model of PD has revealed stronger damage of dopaminergic neurons in the substantia nigra and enhanced microglial activation in LXRβ–/– mice compared to wild-type littermates.(181)
2.3.5. LXR and Multiple Sclerosis
As is obvious from the role of LXR in (neuro)inflammatory processes, LXR modulation also holds promise for MS treatment, and several in vitro and in vivo studies support this assumption. In wild-type mice, treatment with the LXR agonist T0901317 (31) promoted expression of the myelin components myelin basic protein and proteolipid protein, while its effects were lost in LXR double knockout animals suggesting LXR involvement in the regulation of these important neural proteins.(164) Similar observations were made in primary cerebellar cultures.(164) LXR signaling was also found to be important to regulate cholesterol homeostasis in OLs which mediate remyelination.(182) T0901317 (31) treatment of OLs enhanced LXR-regulated gene expression and cholesterol efflux.(182) Overall, these results point to a therapeutic potential of LXR in MS but may be compromised by the limited selectivity of LXR agonist T0901317 (31), which is also an inverse ROR agonist.(180) A recent study(183) has provided further evidence for a therapeutic role of LXR in MS and indicates the importance of LXR signaling for a pro-inflammatory to anti-inflammatory switch of microglia in MS lesions which is needed for repair. After demyelination, myelin and cell debris have to be cleared by phagocytosis requiring a pro-inflammatory response before repair mechanisms are initiated in an anti-inflammatory phase.(183) LXR signaling appears to be important in this switch and to provide cholesterol for remyelination.(183) In line with this, levels of the LXR ligand 27-hydroxycholesterol, LXR activity, and LXR-regulated gene expression were induced in human macrophages after myelin phagocytosis in vitro.(184) Autopsies from active human MS lesions confirmed increased LXR signaling and upregulation of ABCA1 and ApoE.(184) Moreover, LXR has been suggested to involve in T cell differentiation to Th17 cells which are key cellular factors of MS pathology.(185) LXR knockout in EAE mice resulted in enhanced Th17 cell differentiation, whereas the LXR activators T0901317 (31) and GW3965 (32) decreased Th17 cell differentiation.(185) In line with this, IL-17 secretion was reduced in wild-type mice upon LXR agonist treatment.(185) In vitro, T0901317 (31) and GW3965 (32) dose-dependently inhibited Th17 cell differentiation which was also observed upon overexpression of either LXRα or LXRβ. T cells from mice with LXRα, LXRβ, or dual knockout revealed the opposite effect.(185)
2.3.6. LXR Ligands
Several potent LXR ligands have been developed as valuable tools and experimental drugs (Scheme 3). The most widely used LXR reference agonists T0901317 (31)(186) and GW3965 (32)(187) activate both LXR subtypes with similar potencies. Activation of brain LXR has been demonstrated for both compounds in animal models, e.g., by increased expression of LXR-regulated genes in the CNS.(171,173,178) T0901317 (31) also is an inverse ROR agonist,(180) which potentially affects outcomes of in vivo studies. AZ12260493 (33) is another agonist of both LXRs, while BMS779788 (34)(188) and WAY252623 (also termed LXR623, 35)(189) exhibit a slight LXRβ preference. Development of LXR ligands with a pronounced subtype selectivity has been hindered by the high similarity of LXRα and LXRβ providing a remaining challenge for future LXR ligand design. The functionally selective LXRβ agonist 36(190) presents as a successful example to overcome the lack of subtype selectivity. It exhibits markedly higher LXRβ activation efficacy (104%) compared to the LXRα subtype (31%) and was developed for the potential treatment of AD-related pathologies based on the hypothesis that LXRβ preference might avoid hepatic side effects but exhibit full therapeutic efficacy in the brain. 36 was brain-penetrant in mice and rhesus monkeys and increased CNS levels of ABCA1 and ApoE. As hypothesized, no adverse effects on liver triglycerides were observed upon treatment with 36 in either species. In Tg2576 mice overproducing Aβ peptides, 36 caused a reduction of Aβ levels in the brain and improved locomotor activity. In rhesus monkeys, 36 induced a 3-fold increase in brain ApoE levels, while a related compound with high P-gp efflux ratio did not alter ApoE indicating that the effect of 36 was mediated by brain LXR activation. 36, therefore, appears as very promising tool to study LXRβ activation in neurodegeneration with reduced adverse effects of hepatic LXRα agonism.
Scheme 3
Scheme 3. Selected LXR Ligands
2.3.7. Conclusion
As a key regulator of cholesterol homeostasis and anti-inflammatory transcription factor, LXR has attracted attention as a potential target in AD and MS (Table 3). Anti-inflammatory effects in microglia have been demonstrated for LXR activation, and a role in AD is rationalized by the LXR-dependent regulation of ApoE expression, although some observations on LXR in AD models are controversial. LXR agonist tools with sufficient BBB penetration are available, and several studies support the potential of pharmacological LXR activation in AD and MS treatment. Some promising observations, especially regarding anti-inflammatory effects, are compromised by the use of the LXR agonist 31 as tool, which also has considerable potency as an inverse ROR agonist. Among the two LXR isoforms, LXRβ activation has shown greater therapeutic potential in neurodegeneration and less adverse hepatic effects, but fully subtype selective LXR agonists to exploit this potential are lacking, and novel LXR modulators are needed. The functionally selective and brain penetrant LXRβ agonist 36 is a promising example of a next-generation tool to capture the effects of LXRβ activation in the CNS.
Table 3. Summarized Observations on LXRs in Neurodegeneration
| LXRα (= NR1H3; also known as RLD-1) and LXRβ (= NR1H2; also known as UNR, NER, and RIP15) | |
|---|---|
| LXRs in AD | LXR activation ameliorated and LXR knockout enhanced the inflammatory response of microglia to Aβ.(166,167) |
| LXR knockout in transgenic AD mice increased Aβ plaque burden and plaque size.(166) | |
| Observations regarding effects of LXR activation on Aβ levels are inconsistent.(167,171−173) | |
| Long-term LXR agonist treatment improved cognitive function in transgenic AD mice.(177) | |
| LXRs in PD | LXRβ knockout in MPTP-induced PD enhanced microglial activation and dopaminergic neuron damage.(181) |
| LXRs in MS | LXR activation promoted expression of myelin components (myelin basic protein, proteolipid protein).(164) |
| LXR signaling was found to be important in regulating cholesterol homeostasis in (myelinating) OLs(182) and to provide cholesterol for remyelination.(183) | |
| In EAE, LXR knockout enhanced and LXR agonist treatment decreased Th17 cell differentiation.(185) | |
2.4. Vitamin D Receptor (VDR)
2.4.1. Overview
The vitamin D receptor (VDR, NR1I1) is a cellular sensor for vitamin D with 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) as the main endogenous ligand.(150) It binds the DR3 response element as a heterodimer with RXR. VDR is essentially involved in the regulation of vitamin D and calcium homeostasis by controlling expression of crucial enzymes for vitamin D biosynthesis and degradation.(150)
2.4.2. VDR in Neurodegenerative Diseases
The importance of calcium homeostasis in the neuronal system for Ca2+ signaling provides a link between VDR, neuronal function, and neurodegeneration.(191) Additionally, VDR has been ascribed a cell-protective role against toxic metabolites(150,192,193) that might contribute to neuroprotective effects. In the brain, VDR is expressed in neurons and glial cells,(194) and VDR knockout in mice caused motor impairment without affecting cognitive function.(195)
In recent years, a number of reports on VDR-mediated beneficial effects in neurodegenerative diseases have accumulated. Most notably, VDR genetic polymorphisms in humans were correlated with AD or PD, among which one single-nucleotide polymorphism (SNP) showed correlation with both diseases,(196−198) suggesting VDR as a potential susceptibility gene. Genetic polymorphisms of VDR were also found in MS patients.(199) Evidence for the importance of sufficient vitamin D levels in AD, PD, and MS also results from epidemiological and clinical studies.(199−204) In PD, vitamin D supplementation appears beneficial,(200,202) and a correlation between vitamin D deficiency and AD is proposed(201) as epidemiological studies have revealed high prevalence of hypovitaminosis D(201) in AD patient populations. Moreover, prospective studies involving samples of up to 7 million individuals found a correlation between high vitamin D levels and decreased MS risk.(203,205) Altered expression of AD-associated VDR-regulated genes was detected in the brains of mice with hypovitaminosis D,(206) suggesting that low vitamin D levels affect gene expression in the brain.
In vitro, a protective potential of VDR signaling in neuronal cell populations including astrocytes as brain immune cells has been demonstrated in several studies.(207−210) Moreover, it has been proposed that Aβ formed in AD suppresses VDR expression, while administration of vitamin D counteracted this effect.(211) Vitamin D was also found to inhibit LPS-induced astrocyte activation in vitro and in rats,(210) suggesting an anti-neuroinflammatory potential. In line with this, in vivo studies have reported therapeutic effects of vitamin D and analogues in EAE.(212) In the context of PD, diminished VDR expression was detected in the 6-OHDA-induced and the preformed fibril (PFF) injection rodent models of PD.(213) The reduced VDR activity resulted in decreased P-gp levels, which is thought to be important for clearance of intracerebral α-synuclein load in PD.(213) Treatment with 1,25(OH)2D3 counteracted these effects and restored VDR and P-gp activity.(213)
2.4.3. VDR Ligands
Despite promising preliminary data, the potential of VDR as a therapeutic target for neurodegenerative diseases remains to be validated. Several potent (up to sub-nanomolar EC50 and Kd values) and selective VDR modulators (37–41, Scheme 4) including vitamin D analogues and nonsteroidal compounds are available.(214) They can serve for further functional in vivo studies in the context of neurodegeneration. Adverse effects on calcium homeostasis may, of course, limit a long-term therapeutic VDR modulation in neurodegenerative diseases, but extensive efforts in medicinal chemistry(214) have provided potent VDR modulators with low calcemic effects in vivo (e.g., 39) that might overcome this obstacle.
Scheme 4
Scheme 4. Potent and Selective VDR Ligands (Agonists 37–40; Antagonist 41) from the Literature(214−217) as Potential Tools for Functional Studies in Neurodegeneration
2.4.4. Conclusion
Disease-associated SNPs of VDR and the correlation between vitamin D levels and incidence of neurodegenerative diseases provide the strongest evidence for a potential involvement of VDR in neurodegeneration (summarized in Table 4), and motor impairment observed in VDR knockout animals further supports this assumption. However, mechanistic understanding of VDR involvement in neurodegenerative diseases is incomplete, and studies on effects of pharmacological VDR modulation in this context are limited despite the availability of multiple potent and selective VDR modulators. Although involvement of brain VDR in the observed effects, for example, regarding anti-neuroinflammatory activity has been demonstrated, contributions of peripheral VDR activation remain to be evaluated, and adverse effects of systemic VDR activation must be considered.
Table 4. Summarized Observations on VDR in Neurodegeneration
| VDR (= NR1I1) | |
|---|---|
| VDR in AD | Genetic polymorphisms of VDR were correlated with AD.(196) |
| High prevalence of hypovitaminosis D in AD patients.(201) | |
| Low vitamin D levels altered expression of AD-associated genes in mice.(206) | |
| VDR in PD | Genetic polymorphisms of VDR were correlated with PD.(197,198) |
| Beneficial effects of vitamin D supplementation.(200,202) | |
| VDR expression was diminished in 6-OHDA-induced PD.(213) | |
| VDR knockout in mice caused motor impairment without affecting cognitive function.(195) | |
| VDR in MS | Genetic polymorphisms of VDR were correlated with MS.(199) |
| High vitamin D levels correlated with lower MS risk.(203,205) | |
| VDR activation inhibited LPS-induced astrocyte activation in vitro and in rats.(210) | |
| VDR activation ameliorated EAE.(212) | |
2.5. Retinoid X Receptors (RXR)
2.5.1. Overview
RXR belongs to the second subfamily of nuclear receptors and has the typical NR structure. It exists in three subtypes which are encoded by independent genes(218) but still exhibit very high structural similarity, especially in the LBD. The amino acids, which are responsible for the formation of the ligand binding site, are identical in all three subtypes.(219−221) A key feature of RXR is that it acts as a universal heterodimer partner for many other NRs.(21) These heterodimers are distinguished between permissive (e.g., PPAR/RXR, FXR/RXR and LXR/RXR) and nonpermissive heterodimers (e.g., RAR/RXR)(21) (Figure 2). Nonpermissive heterodimers can only be activated by ligands of the heterodimer partner and not by an RXR agonist alone.(21) In contrast, permissive heterodimers can be activated by ligands of RXR and by ligands of the heterodimer partner, and are synergistically activated in the presence of ligands for both partners.(21)
Figure 2
Figure 2. Role of RXR in NR heterodimers. Permissive heterodimers respond to RXR ligands and to ligands of the heterodimer partner. The presence of ligands for both partners causes synergistic activation. Nonpermissive heterodimers can only be activated by ligands of the heterodimer partner.(21)
Owing to this important role in the NR network, at least one subtype of RXR is expressed in every cell that has a nucleus,(218,222) but the subtype distribution differs. In mice, RXRα was found distributed over the whole body but with particularly high expression in the liver, spleen, epidermis, and kidney.(218,223) For RXRß, no explicit expression pattern could be observed, resulting in the assumption that this subtype is almost ubiquitous.(218,223) Regarding neurodegenerative diseases, it is important to mention that, in contrast to the other two subtypes, higher CNS localization was observed for RXRγ. Additionally, this subtype is found in heart muscles, adrenal glands, and muscle cells.(218,223) Within the CNS, there is no distinct distribution. RXRγ is expressed in the striatum, parts of the amygdala, the spinal cord, and in the hypothalamus.(224,225) A particularly high expression was found in basal ganglia, and an association with motor function and addiction has been suggested.(226) Especially noteworthy is the high expression of RXRγ in glial cells,(226) as these cells are involved in pathophysiological processes in neurodegenerative diseases.(227,228)
Because of its crucial involvement in numerous (patho-)physiological processes as a universal NR heterodimer partner, the pharmacological potential of RXR may be very high. In addition to the established role of RXR activation in the field of cancer therapy,(222) the role of RXR in neurodegenerative diseases has been intensively studied in recent years. Therein, RXR involves in neuroprotective, neuroinflammatory, and regenerative processes regulated by its heterodimers.(229) Especially for the treatment of AD, MS, and PD, RXR is evolving as an attractive target.
2.5.2. RXR in Alzheimer’s Disease
One of the major risk factors for the development of AD is ApoE, especially the ApoE-ϵ4 variant.(230−234) Together with the ABCA1, ApoE regulates the lipid and cholesterol transport in the CNS.(235) ABCA1 mediates the cellular efflux of phospholipids and cholesterol toward ApoE.(236) It has been proposed that ApoE inadequately equipped with lipids and cholesterol affects the accumulation and transport of Aβ.(235,237,238) Both the ApoE and the ABCA1 genes are under transcriptional control of the PPARγ/RXR- and LXR/RXR-heterodimers.(230) For this reason, an RXR agonist could exhibit a dual effect through the simultaneous activation of both heterodimers, since both heterodimers are permissive.(23)
Therapeutic effects of RXR agonists have been observed in common preclinical models of AD. In APP/PS1 mice, acute treatment with bexarotene (42) caused a removal of diffuse and compact Aß plaques in the cortex and hippocampus, elevated levels of ApoE, ABCA1, and ABCG1, reduced soluble and insoluble Aβ levels, counteracted cognitive and behavioral deficits and restored cognition and memory.(239) The bexarotene (42)-treated APP/PS1 mice also showed an improved hippocampal function, and in total, the Aβ plaques were reduced by 75%.(239) This acute and chronic efficacy of RXR activation with bexarotene (42) in AD in both early and late stages presents as a very attractive and promising therapeutic strategy. However, four independent groups, despite also observing therapeutic effects, failed to reproduce these findings thoroughly.(240−243)
The effects of bexarotene (42) in AD have also been investigated in two small clinical studies. A phase 1 trial with 12 patients receiving either 450 mg/day bexarotene (42) or placebo reported that only a very small proportion of bexarotene (42) enters the CNS. Bexarotene (42) treatment only slightly elevated ApoE levels in CSF and had no effect on the synthesis, clearance, or total levels of Aβ in CSF.(244) In a small, double-blind, placebo-controlled phase 2 trial, 20 patients with AD were randomized to receive 300 mg/day of bexarotene (42) or placebo for 4 weeks.(245) No difference regarding composite or regional Aβ burden was observed between bexarotene (42) and placebo when all patients were included in the analysis.(245) However, ApoE-ϵ4 noncarriers showed reduced Aβ burden in all measured cortical regions after bexarotene (42) treatment compared to placebo.(245) In addition, an observed correlation between reduced cortical Aβ and an increasing serum level of Aβ1–42 potentially indicates an excretion of soluble Aβ forms from brain to blood.(245) This short-term trial was not powered to detect cognitive changes, however.(245)
2.5.3. RXR in Parkinson’s Disease
Similar to AD, involvement of RXR in PD is connected with permissive RXR heterodimer formation. In the case of PD, the permissive RXR/Nurr1 heterodimer is most relevant due to the key role of Nurr1 in PD (see section 2.7.2).(2,246)
2.5.4. RXR in Multiple Sclerosis
An involvement of RXR in MS is evident from the fact that its expression is elevated upon CNS damage.(247) An increased expression of RXRγ in OPCs, which develop into adult OLs and are responsible for the formation of the myelin layer, has been detected in MS lesions.(227) OLs can repair damage to myelin sheaths caused by MS-associated autoimmune inflammation to a certain extent and thus may have regenerative potential.(227) The increased RXRγ expression was observed both in rats with toxin-induced central demyelination and post mortem in human tissue samples.(227) Moreover, RXRγ knockout mice displayed significantly less differentiated OLs in lesions after toxin-induced demyelination compared to wild-type animals.(227)
A second possible mechanism of RXR involvement in MS(248) refers to the fact that myelin fragments resulting from demyelization inhibit OPC differentiation.(249,250) Removal of these fragments represents an important step in the regeneration of CNS damage. Macrophage-specific RXRα knockout mice exhibited reduced myelin phagocytosis capacity after induced demyelination and delayed OPC differentiation,(248) suggesting involvement of RXR in this process together with its heterodimer partners PPAR and LXR (see sections 2.1 and 2.3). Moreover, an interesting reversal of functional defects in myelin phagocytosis by MS monocytes upon bexarotene (42) treatment was observed in patient-derived monocyte samples.(248)
The effect of RXR activation in MS was examined in several preclinical models. In vitro, 9-cis RA (43) exhibited anti-inflammatory effects on microglia and astrocytes by inhibiting the production of pro-inflammatory cytokines, such as TNFα and IL-1ß.(251) RXR activation hence counteracted neuroinflammation and might intervene in the acute phase of the disease. Furthermore, 9-cis RA (43) promoted the differentiation of OPCs ex vivo and enhanced myelin basic protein production.(227) In focal toxin-induced demyelination in aged rats, 9-cis RA (43) enhanced expression of myelin basic protein mRNA in lesions and accelerated remyelination.(227) In addition to 9-cis RA (43) and bexarotene (42), the second-generation rexinoid IRX4204 (90, see section 2.7.2.6) has been studied in several preclinical models of MS. It alleviated the symptoms of EAE in mice and supported the differentiation of OPCs from mouse brains to OLs.(252) In focal toxin (ethidium bromide) induced demyelination in rats (one-year-old), IRX4204 (90) treatment caused an increase in CNS remyelination,(252) and in a mouse model of nonimmune-mediated demyelination, IRX4204 (90) exhibited neuroprotective activity by directly affecting demyelinated axons.(252)
2.5.5. RXR Ligands
As outlined above, RXR has a central role in the network of NRs as a heterodimer partner. From this unique characteristic, a potential involvement of RXR in multiple regulatory systems can be inferred since the majority of RXR heterodimers is permissive, meaning that they can be activated by RXR agonists.(253) In addition, ligand-dependent allosteric modulation between the heterodimer partners is discussed.(26) The resulting therapeutic potential of RXR modulation in multiple indications has stimulated considerable efforts in RXR ligand development. In addition to the high similarity of the three RXR isoform LBDs,(221) the RXR ligand binding sites are very lipophilic and provide little potential for polar ligand–protein interactions.(221,222) Consequently, the majority of RXR ligands are exceptionally lipophilic.
Very early on, metabolites of vitamin A were suspected as natural RXR ligands, and based on this, 9-cis RA (43, Scheme 5) was identified as a high-affinity ligand.(107,254) Reported EC50 values for 9-cis RA (43) vary depending on the test system between 1.7 and 200 nM for all RXR subtypes.(222,254−258) Because of its low endogenous levels, the physiological relevance of 9-cis RA (43) is controversially discussed, however. Exogenous 9-cis RA (43) has therapeutic relevance (as alitretinoin) to treat chronic hand eczema and skin lesions in connection with Kaposi’s sarcoma(259,260) and is studied for the treatment of atopic dermatitis and psoriasis.(261) 9-Cis-13,14-dihydroretinoic acid (44), another metabolite of vitamin A, activates RXR as well and was detected in mice at relevant levels.(262,263) In addition, several fatty acids were discovered as potential endogenous RXR ligands including docosahexaenoic acid (DHA, 45), oleic acid (46), palmitic acid (47), and stearic acid.(221,222,256,264,265) The potency of these fatty acids on RXR is limited (micromolar range), however, and despite considerable concentrations found in plasma and even the brain, a physiological relevance remains to be demonstrated.
Scheme 5
Scheme 5. Selected RXR Ligands
The first potent synthetic RXR agonists were based on the structure of 9-cis RA (43), which conforms well to the L-shaped ligand binding pocket of RXR. The most prominent synthetic RXR agonist is bexarotene (42) is the only synthetic RXR ligandthat has received drug approval to date. It is used as a second-line therapy in the treatment of cutaneous T cell lymphoma.(222,266,267) Bexarotene (42) is a pan-RXR agonist with similar potency on all three subtypes (EC50: RXRα: 33 nM, RXRβ: 24 nM, RXRγ: 25 nM)(268) and comprises nonfavorable physicochemical properties(117) with exceptionally high lipophilicity (logP 6.9), low solubility, and poor pharmacokinetics.(117,269,270) In addition, bexarotene (42) is associated with risks/adverse effects(271) such as severe disturbances in lipid homeostasis (elevated triglyceride and cholesterol levels), leukopenia, hypothyroidism, and an increased risk of acute pancreatitis. From bexarotene (42), several other rexinoids were developed such as SR11237 (48, EC50: RXRα: 29 nM, RXRβ: 98 nM, RXRγ: 232 nM),(272) LG100268 (49, EC50: 3–4 nM),(273) PA024 (50, EC50: RXRα: 3 nM, RXRβ: 24 nM, RXRγ: 8 nM),(272) NEt-3IP (51, EC50: RXRα: 32 nM, RXRβ: 36 nM, RXRγ: 376 nM),(274) and NEt-3IB (52, EC50: RXRα: 0.58 nM, RXRβ: 23 nM, RXRγ: 3 nM).(274) Derived from the unselective PPAR agonist Wy14-643 (14),(275) the RXR agonist 53(117) has been developed as a potent next-generation RXR ligand with strong selectivity, superior physicochemical properties, and improved pharmacokinetics. RXR antagonists were obtained from rexinoid scaffolds by introduction of bulky side chains.(276,277) Representative RXR antagonists useful as tool compounds are HX531 (54, IC50: RXRα: 1 μM), LG100754 (55, IC50: RXRα: 16 nM), and UVI3003 (56, IC50: RXRα: 0.24 μM).(276)
Progress has recently been made in subtype selective targeting of RXR. The natural product valerenic acid (57) was discovered as an RXRβ agonist with functional preference. In addition to a lower EC50 value for RXRβ activation (EC50: RXRα: 27 μM, RXRβ: 5.2 μM, RXRγ: 43 μM) valerenic acid (57) exhibits remarkably higher efficacy on the RXRβ subtype (fold activation: RXRα: 9-fold, RXRβ: 69-fold, RXRγ: 4-fold).(278) Moreover, computational de novo design(279) has yielded biphenyl-based RXR modulators, which could be tuned in their subtype-preference profile as exemplified by the RXRβ preferential compound 58.(280) Together, these results demonstrate that RXR subtype selectivity can be achieved despite their high LBD similarity.(221)
2.5.6. Conclusion
Because of its ability to act as a universal heterodimer partner for multiple other NRs, RXR is involved in various aspects of neurodegenerative diseases (summarized in Table 5) and has been intensively studied for this role in recent years. Despite some controversial reports, therapeutic effects of pharmacological RXR activation in many preclinical models support a promising therapeutic potential of RXR especially in AD and MS. Most remarkably, pharmacological RXR activation reduced Aβ plaques in cortex and hippocampus of AD mice, promoted remyelination in mouse models of MS, and reversed functional defects of MS monocytes in myelin phagocytosis. However, available RXR agonists such as bexarotene (42), 9-cis RA (43), or IRX4204 (90), though exhibiting remarkable potency, have several limitations. BBB penetration was found to be very low for bexarotene (42) and is likely poor for the other structurally related rexinoids due to their common carboxylic acid group. The low CNS bioavailability of the RXR agonist tools used in the preclinical studies might raise the question of whether the attractive effects were actually mediated by RXR activation in the brain. However, several studies have included knockout or antagonist control experiments, suggesting that RXR in the CNS is at least in part involved in the therapeutic activities. Moreover, the involvement of the universal heterodimer partner RXR in multiple nuclear receptor signaling systems and the associated adverse effects that were, for example, observed with bexarotene (42), demand the development of subtype selective RXR modulators. The recent discovery of valerenic acid (57) as a selective RXRβ agonist(278) demonstrates that this selectivity can be achieved despite remarkable similarity of the three RXR isoforms.(221) Hence, a lot of further research is needed to enable subtype selective RXR activation in the brain and to capture the full potential of RXR modulation in neurodegenerative diseases.
Table 5. Summarized Observations on RXR in Neurodegeneration
| RXRα (= NR2B1), RXRβ (= NR2B2; also known as H-2RIIBP and RCoR-1) and RXRγ (= NR2B3) | |
|---|---|
| RXR in AD | In APP/PS1 mice, bexarotene (42) treatment (3, 7, or 14 days) reduced Aβ levels and caused removal of Aβ plaques, elevated ApoE, ABCA1, and ABCG1 levels, restored cognition and memory function, and improved hippocampal function.(239) |
| In human patients, bexarotene (42) treatment slightly elevated ApoE levels in CSF but had no effect on synthesis, clearance, or total levels of Aβ. ApoE-ϵ4 noncarriers showed reduced Aβ burden.(244,245) | |
| RXR in MS | RXRγ-knockout mice had less differentiated OLs in lesions after toxin-induced demyelination.(227) |
| RXRα-knockout mice exhibited reduced myelin phagocytosis after demyelination and delayed OPC differentiation.(248) | |
| Bexarotene (42) reversed functional defects of MS patient monocytes in myelin phagocytosis.(248) | |
| 9-cis RA (43) exhibited anti-inflammatory effects on microglia and astrocytes by inhibiting the production of pro-inflammatory cytokines, such as TNFα and IL-1ß.(251) | |
| 9-cis RA (43) and IRX4204 (90) caused CNS remyelination in young and aged rats after toxin-induced demyelination.(227,252) | |
| IRX4204 (90) alleviated symptoms of EAE in mice and promoted differentiation of OPC.(252) | |
| RXR in PD | See permissive RXR/Nurr1-heterodimer. |
2.6. Tailless Homologue (TLX, NR2E1)
2.6.1. Overview
The orphan NR TLX (NR2E1) is one of the least studied and most elusive nuclear receptors. It is considered a master regulator of neural stem cell (NSC) maintenance(281) and is evolutionarily conserved in vertebrates and invertebrates. TLX was found to exhibit an essential role in embryonal brain development, and high TLX expression in adults was detected exclusively in quiescent and rapidly dividing NSCs in neurogenic regions as well as in retinal progenitor cells.(282−285)
Mechanistically, TLX appears to differ from other nuclear receptors in a number of aspects. In line with its role in maintaining NSCs in a proliferating state and the underlying suppression of pten and p21, TLX was found to act mostly as a negative regulator of gene expression. It binds to the NR response element sequence AAGTCA as a monomer with high affinity(286) and according to current knowledge differs also in its corepressor recruitment profile from most other NRs as it strongly binds atrophin, lysine-specific histone demethylase 1A (LSD-1), and histone deacetylases to inhibit gene expression.(286−291) Structurally, TLX comprises the typical architecture of NRs despite a shorter LBD that lacks the first two of 12 helices which are present in most NRs.(286) Early modeling approaches suggested that TLX may possess a ligand binding pocket within the LBD,(286,292) but evidence from a cocrystal structure supporting this assumption is lacking. A TLX apo structure revealed the terminal α helix H12 of TLX bound at the canonical coactivator binding site of nuclear receptors indicating an autorepression.(293) This autorepressed state resembles other NRs with repressor activity such as the TLX-related photoreceptor-specific nuclear receptor (PNR, NR2E3)(294) and the dosage-sensitive sex-reversal adrenal hypoplasia congenital critical region on the X chromosome gene 1 (Dax-1, NR0B1).(295) The putative ligand binding site of TLX is mostly blocked by bulky hydrophobic residues in the apo structure.(291,293) Molecular dynamics and subsequent mutagenesis studies have suggested a potential binding site (for rexinoids) inside the TLX LBD close to the interface of helices H3 and H11.(291) This site has a higher solvent exposure than the ligand binding pockets of common NRs and is not present in the apo structure but requires conformational changes of H11 or H3 depending on the ligand type.(291,293)
2.6.2. TLX in Neurodegeneration
Despite limited knowledge on TLX and the lack of TLX modulator tools for functional studies, there is preliminary evidence for a great potential of TLX in neurodegenerative diseases. In the brain, TLX regulates the maintenance of NSC populations and neurogenesis.(281,290) It governs behavior and activation of NSCs(281) through directly controlling the expression of the tumor suppressor pten and the cyclin-dependent kinase inhibitor p21, thereby enabling re-entry in the cell cycle.(281,284,286) Accordingly, the putative TLX activator oleic acid (46) was recently shown to induce NSC mitosis and neurogenesis in mice.(296) Thus, maintaining NSCs in the brain in a proliferating, self-renewing state and preventing their differentiation appear to be key roles of TLX.(281,282,297−299) NSCs are found in at least two main regions of the adult (human) brain, the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle, from where NSCs initiate the formation of new neurons.(281,282,300) TLX appears to be a key regulator of this process by maintaining a balance between proliferating NSCs and differentiated neurons.(281,282,300) The absence of TLX, accordingly, caused an entire loss of neurogenesis.(301) A number of knockout studies in rodents have revealed promising links of TLX to neurological and neurodegenerative diseases. TLX knockout led to limbic defects, hyperactivity, and violent behavior in adult mice.(281,302,303) Concomitantly, active neurogenic regions in the brains of these mice showed severe deficits.(281,304) NSCs from TLX knockout mice were unable to proliferate and self-renew, while an ectopic expression of TLX efficiently rescued this ability.(281,282) A brain-specific TLX overexpression in mice led to improved learning capacity and memory function.(305)
These observations from in vitro and in vivo studies together draw a picture of TLX as a crucially important regulator of neuronal health and neuro-regeneration, and demonstrate an involvement of the orphan NR in spatial learning and cognitive functions during adolescence and adulthood.(281,306−308) Moreover, TLX mutations in humans are linked to microcephaly and mental diseases such as bipolar disorders and schizophrenia.(281,309) A recent study observed a correlation between schizophrenia risk and certain TLX haplotypes that were predicted to affect the expression rate of TLX,(310) ascribing the orphan NR also a key role in mental health. Overall, compelling evidence points to a great therapeutic potential of targeting TLX in neurodegeneration and neurological diseases.
In addition to its involvement in neuronal and retinal function, TLX has been associated with glioblastoma development, the most common and a highly aggressive brain tumor.(311−313) The orphan NR was found overexpressed in tumor stem cells of glioblastoma,(312) while TLX knockdown decreased tumor progression and enhanced survival in a xenograft tumor model in mice.(314) TLX modulators, therefore, might hold strong potential in this context as well. However, there is no evidence that ectopic TLX overexpression in animal models promotes cancer development,(291) which is an important aspect for pharmacological targeting of TLX in neurodegeneration.
2.6.3. TLX Ligands and Modulators
A number of studies have demonstrated that TLX activity can be modulated by small molecule ligands, and a few TLX modulators with mostly weak potency (micromolar range) have been described(286,291,292,315) (Scheme 6). Benod et al.(292) were the first to report small molecule modulators of TLX from a medium-throughput screening campaign. By differential scanning fluorimetry with the recombinant TLX LBD protein, they identified 190 primary hits from a library of 20 000 compounds. Three compounds (famprofazone, ccrp1 (59); ccrp2 (60); dydrogesterone, ccrp3 (61)) showed activity on TLX in an orthogonal cellular reporter gene assay. In another study,(315) the activity of famprofazone (59) and ccrp2 (60) (ccrp3 (61) was not tested) could not be reproduced, however. Dueva et al.(315) applied a computational approach to TLX ligand discovery and reported 62–64 as TLX modulators in a cellular setting. Orthogonal validation of these compounds as TLX ligands is pending, however, and they comprise PAINS suspect elements. Retinoids (ligands of the nuclear retinoic acid receptors, RARs) have recently been proposed to act as TLX modulators, too. In vitro, certain natural (all-trans retinal, ATRAL (65)) and synthetic (BMS453 (66); CD1530 (67)) compounds showed TLX activation or inverse agonism with potencies ranging approximately between 0.2 μM and 2 μM.(291) Retinoid efficacy in TLX activation (∼5-fold, BMS453 (66)) and repression (∼4-fold, ATRAL (65)) was limited, however. NMR experiments were employed to orthogonally validate a direct interaction between TLX and the retinoids, which revealed chemical shift perturbations and line broadening.(291) Another recent study(296) has discovered oleic acid (46) as a putative endogenous TLX ligand that is capable of switching TLX activity from transcriptional repression to cell cycle activation and was shown to be present in human NSCs.
Scheme 6
Scheme 6. TLX Ligands Reported in the Literature(291,292,315)
2.6.4. Conclusion
Despite a very limited understanding of TLX, the essential regulator of NSC homeostasis holds remarkable promise in neurodegenerative diseases (summarized in Table 6). However, owing to the lack of TLX modulators as tools, functional understanding of TLX is incomplete, and insights in its (patho-)physiological role stem only from knockout experiments. Current evidence of TLX mutations disrupting neurogenesis and knockout causing abnormal brain development and behavioral deficits points to a high potential of targeting TLX for regenerative approaches in neurodegeneration. Therein, the exclusive expression of TLX in certain brain regions may suggest few adverse effects of TLX modulation since no other tissues would be affected. However, the known TLX ligand space is very limited and somewhat controversial. Biochemical and biophysical characterization of most putative TLX modulators is not comprehensive. Broad reproduction of their activities in various settings and orthogonal validation is pending. Despite preliminary data, binding sites and the molecular mode-of-action remain elusive for TLX. With their limited potency, efficacy, and selectivity, and their unclear modes of action, the available TLX ligands are insufficient for pharmacological evaluation and validation of the orphan NR. More potent, selective, and broadly profiled TLX agonists and inverse agonists are required as pharmacological tools for target validation. The development of potent TLX ligands as highly profiled tools for functional studies on TLX is imperative.
Table 6. Summarized Observations on TLX in Neurodegeneration
| TLX (= NR2E1; also known as TLL and XTLL) | |
|---|---|
| TLX in neurodegeneration | TLX mutations in human were associated with microcephaly and mental diseases.(281,309) |
| TLX regulates the maintenance of NSCs and neurogenesis.(281,290) | |
| TLX maintains a balance between proliferating NSCs and differentiated neurons.(281,282,300) | |
| TLX knockout led to defects in neurogenesis,(281,304) limbic defects, hyperactivity, and violent behavior in adult mice.(281,302,303) | |
| Brain-specific TLX overexpression improved learning capacity and memory function.(305) | |
2.7. NR4A Receptors
2.7.1. Nur77 (NR4A1)
2.7.1.1. Overview
As the first member of the NR4A subfamily of NRs, Nur77 was originally identified as nerve growth factor-induced clone B (NGFI-B)(316) and is an orphan nuclear receptor since no endogenous ligands are known so far. Nur77 was thought to be a ligand-independent transcription factor due to its closed and tightly packed conformation of the LBD in which the canonical ligand binding pocket is occupied by bulky hydrophobic amino acids that are conserved among the three NR4A subfamily members.(317) The resulting autoactivated conformation (Figure 3c) renders Nur77 (and the related NR4A receptors Nurr1 and NOR-1) as a constitutively active transcriptional inducer with high transcriptional activity in the absence of a ligand. Nur77 can act in three forms, as a monomer on NGFI-B response elements (NBRE), as a homodimer on Nur response elements (NurRE), which were first detected in the promoter region of the proopiomelanocortin (POMC)(318) gene, or as a heterodimer with an RXR on DR5 response elements.(319−321) Nur77 is widely expressed in several tissues including the pituitary gland, adrenal gland, thyroid, liver, testis, ovary, thymus, muscle, lung, and prostate(29) but also in the nervous system with the highest levels in the cerebral cortex and hippocampus.(322) In contrast to Nurr1, it is highly expressed in target areas of dopaminergic neurons such as the striatum, nucleus accumbens, and prefrontal cortex. Interestingly, Nur77 mRNA was not found in the prenatal CNS but only in the adult brain.(323) The functions of Nur77 are manifold and appear to be tissue specific. In metabolic diseases like diabetes, it seems to participate in the regulation of blood glucose levels since genetic deletion of Nur77 in mice increased insulin resistance.(324,325) Also several inflammatory conditions such as asthma,(326) atherosclerosis,(327,328) arthritis,(329) and sepsis(330) are linked to Nur77 activity. Additionally, Nur77 is overexpressed in multiple solid tumors and plays a pro-oncogenic role in cancer (reviewed in Beard et al.(331)). Moreover, Nur77 was shown to induce apoptosis by targeting mitochondria, whereby it translocates from the nucleus to the cytoplasm in an RXRα regulated fashion,(332,333) suggesting that Nur77 also exhibits activities via non-transcriptional mechanisms.
Figure 3
Figure 3. Comparison of the crystal structures of “classical” nuclear receptors (RXRα) and NR4A receptors (Nur77). (a) The apo structure of the RXRα LBD (pdb 3R29) in complex with the corepressor peptide SMRT (magenta) reveals the NR in its inactive state in which the C-terminal α-helix (H12, colored red) comprises the AF-2 in an unordered conformation. (b) The ligand-activated state of RXRα (pdb 3OAP) shows the NR cocrystallized with its endogenous ligand 9-cis RA (43) and the coactivator peptide TIF2 (neon green) with H12 in its active conformation. (c) The apo structure of the Nur77 LBD (pdb 3V3E) reveals the NR in an autoactivated state with H12 coordinated to the LBD core without a bound ligand. (d) Ligand-activated cocrystal structure (pdb 6KZ5) of the Nur77 LBD in complex with agonist Csn-B (68, purple) superimposed with ligand binding pockets and their respective ligands from other Nur77 cocrystal structures revealing other binding sites with high solvent exposure. Csn-B (68, purple) is bound at the dimeric interface, THPN (71, teal, pdb 4JGV) is protruding toward a sub-pocket between H5 and H7, and TMPA (69, blue and orange, pdb 3V3Q) is bound to two different sites. Site A (orange) is located at the interaction site of H12, which resembles the binding pockets identified for covalently bound Nurr1 ligands DHI (83) and PGA1 (80), while site B (blue) constitutes a cavity on the surface close to helices 1, 5, and 8. Alignment and superposition of the structures were performed in MOE 2020.09.
2.7.1.2. Nur77 in Parkinson’s Disease
Growing evidence, mainly from PD models, ascribes Nur77 a role in in neurodegenerative diseases. Although Nur77 knockout mice(334) and rats(335) exhibited only a mild phenotype, they tended to have higher basal locomotor activity. In line with this, a SNP in the Nur77 gene was found to be strongly associated with tardive dyskinesias in a cohort of schizophrenic patients.(336) Several studies further investigated the role of Nur77 in drug-induced dyskinesias and PD models with somewhat controversial results. Still, all studies demonstrate involvement of Nur77 in aberrant dopamine-related behavior.
Full Nur77 knockout in mice displayed beneficial effects on dopamine neuron function.(334) Moreover, the regulation of the neuropeptides enkephalin and neurotensin was shown to be Nur77 dependent in the context of dopamine denervation in 6-ODHA-lesioned mice;(337) however, they remain to be validated as direct Nur77 target genes.(337,338) In two MPTP animal models, Nur77 was downregulated,(339,340) and Nur77 knockout resulted in a sensitization to dopaminergic cell death following MPTP treatment.(340) In drug-induced dyskinesia, induction of Nur77 by administration of RXR agonist DHA (45) following levodopa treatment ameliorated symptoms.(339) The latter was proven with DHA (45) administration in Nur77 knockout mice,(341) which failed to counteract haloperidol-induced dyskinesia pointing toward a potential involvement of the Nur77-RXR heterodimer.
The findings of Rouillard et al.(335) and Wei et al.(342) are hence controversial: Although Nur77 expression is almost negligible in substantia nigra and the ventral tegmental area, rapid upregulation of Nur77 in substantia nigra and midbrain was observed in a 6-OHDA-induced rat PD model with concomitant downregulation of Nurr1 and TH in midbrain.(335) Moreover, Nur77 deficiency decreased dopaminergic neuronal loss in two different rodent PD models.(335) Accordingly, Nur77 protein expression was rapidly upregulated upon 6-OHDA treatment in vitro, and Nurr1 protein expression decreased over time, supporting a contradirectional coupling of these two receptors in the context of neurodegeneration.(342,343) The NMDA receptor antagonist memantine and lentiviral Nur77 knockdown reversed these effects, prevented neurodegeneration by inhibiting Nur77 translocation to the cytosol, and promoted neuroprotection via post-translational modifications of Nurr1.(342)
Contributions of Nur77 to neuroinflammation in the context of PD are more consistent. In microglia, Nur77 expression was reduced upon microglial activation by LPS treatment in vitro and in vivo.(344) Silencing of Nur77 enhanced inflammatory responses and overexpression or activation of Nur77 with the agonist cytosporone B (Csn-B, 68) suppressed pro-inflammatory responses.(344) These anti-inflammatory effects were shown to involve Nur77-mediated inhibition of IκB-α phosphorylation and NFκB repression.(345) Additionally, anti-inflammatory and antioxidant stress effects of Nur77 activity were demonstrated with Csn-B (68) counteracting MPP+-induced inflammation in vitro,(345) and with C-DIM5, a Nur77 and Nurr1 activating compound, diminishing NFκB activity in MPTP/TNF/IFN-treated astrocytes.(343) Of note, Popichak et al. detected compensatory expression of Nur77 and Nurr1 in astrocytes by knocking down either nuclear receptor by RNA interference (RNAi), whereas NOR-1 expression was not affected.(343) Therein, the anti-inflammatory effect of C-DIM5 increased upon Nur77 knockdown, pointing rather toward Nurr1-mediated effects. Double knockdown of both receptors fully prevented the anti-inflammatory activity of C-DIM5. However, direct binding of C-DIM5 to either receptor is only supported by molecular docking studies.
2.7.1.3. Nur77 in Multiple Sclerosis
In the context of MS, Nur77 is expressed during early T cell activation and acts as a key regulator of T cell immunometabolism, which controls the development of aberrant pro-inflammatory T cell responses and autoimmunity.(346) Nur77 deficiency led to enhanced T cell proliferation, and Nur77 knockout in EAE in mice caused earlier disease onset and significantly increased the clinical EAE score.(346) Based on Nur77’s role as a negative regulator of microglial activation, the Nur77 agonist Csn-B (68) was studied in EAE in mice. Treatment with 68 markedly ameliorated disease progression in wild-type mice but not in Nur77 knockout animals and protected from demyelination.(347) As Nur77 restricts T cell activation and T cell-mediated CNS autoimmunity, and acts as regulator of metabolic genes in activated T cells, selective Nur77 agonists may emerge as a new approach to counteract T cell-mediated autoimmune diseases like MS.
2.7.1.4. Nur77 in Alzheimer’s Disease
In AD, there is little evidence for an involvement of Nur77 to date. Expression of alpha 1-antichymotrypsin/serpinA3, a member of the serine protease inhibitor family, was found to be induced by Nur77 as it contains a Nur77 monomer response element in its promoter region.(348) It is involved in acute phase and inflammatory responses but is also known to contribute to the development of AD as it interacts with Aβ peptide and turned out to be a major component of Aβ plaques. Moreover, RXRα and Nur77 were found to translocate from the nucleus to the mitochondria in neurons after Aβ and H2O2 treatment which resulted in apoptosis.(349) Accordingly, treatment with the RXR agonist 9-cis RA (43) reduced apoptosis by blocking the translocation in vitro and in vivo and enhanced B-cell lymphoma 2 (Bcl-2) protein expression.
2.7.1.5. Nur77 Ligands
Although Nur77 is an orphan nuclear receptor, several studies have reported Nur77 modulating small molecules (Scheme 7). Growing evidence from crystal structures supports the assumption of a blocked canonical ligand binding pocket since all known Nur77 ligands to date bind to noncanonical sites on the surface of the LBD (Figure 3d). Among them, the agonist cytosporone B (Csn-B, 68), a natural product, was the first compound shown to directly bind to the Nur77 LBD(350) by glutathione S-transferase-pull-down, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR) binding kinetics, and mutagenesis studies. Two different reporter gene assays in BGC-823 cells, a human gastric cancer cell line, confirmed transactivation of Gal4-Nur77-full-length (fl) (EC50 0.278 nM) and Gal4-Nur77-LBD (EC50 0.115 nM) constructs. No response was observed with Gal4-Nur77-DBD and Gal4-Nur77-Y453A mutant constructs supporting a direct interaction with the Nur77 LBD. In addition to Nur77, binding of Csn-B (68) to the related receptor Nurr1 was observed in NMR perturbation studies, but Nurr1 transactivation by Csn-B (68) was weak.(350,351) Csn-B (68) was also evaluated in vivo where it increased blood glucose levels and induced gluconeogenic genes in wild-type animals but not in Nur77–/– knockout mice. Additionally, Nur77-induced apoptosis by targeted translocation from nucleus to cytoplasm was observed upon treatment of BGC-823 cells with Csn-B (68). Many further studies(352,353) focused on the anticancer activity of Csn-B (68), and systematic structure–activity relationship (SAR) studies on the Csn-B (68) scaffold were conducted which identified the alkyl ester function as a key pharmacophore feature for Nur77 transactivation.(352) Recently, a cocrystal structure (pdb 6KZ5) of Nur77 in complex with Csn-B (68) revealed an unusual pocket at the dimer interface between two LBD molecules(353) (Figure 3d, purple site).
Scheme 7
Scheme 7. Nur77 Ligands Reported in the Literature(325,330,350,354,356,357)
Following the discovery of Csn-B (68) as a direct Nur77 agonist, several derivatives were developed and intensively studied for their modes of action. Effects in the field of metabolic diseases were further investigated in vitro and in vivo with ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA, 69),(325) a neutral antagonist derived from Csn-B (68) with no effect in a Nur77 reporter gene assay. A cocrystal structure (pdb 3V3Q) demonstrated direct binding to two different sites on the surface of the Nur77 LBD. Site A is located between helices 4, 11, and 12 (Figure 3d, orange site), while site B constitutes a cavity on the surface close to helices 1, 5, and 8 (Figure 3d, blue site).
A potential anti-inflammatory compound was developed with the Csn-B (68) derivative n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl]acetate (PDNPA, 70),(330) a competitive inhibitor of the Nur77–p38α interaction via binding to Nur77. The compound prevented phosphorylation of Nur77 and but conserved the ability of Nur77 to inhibit NFκB activity by direct interaction with the NFκB subunit p65 (Figure 4b). Despite also binding to the Nurr1- and NOR-1-LBDs, PDNPA (70) antagonized an NFκB reporter gene assay in a RAW264.7 murine macrophage cell line only in a Nur77-dependent fashion with an IC50 value of 1.6 μM. Ligand binding of PDNPA (70) to Nur77 was confirmed by a cocrystal structure (pdb 4RZG), which revealed binding to site A like TMPA (69), between helices 4, 11 and 12, but PDNPA (70) and TMPA (69) differed in their in vitro and in vivo activities.
Figure 4
Figure 4. NR4A receptor mechanisms of action. (a) The constitutively active NR4A receptors (Nur77, Nurr1, and NOR-1) can directly bind to specific response elements as a homodimer, as a heterodimer with RXR (only Nur77 and Nurr1), or as a monomer. Sumoylation of the respective NR causes monomerization, and these monomers activate NBRE. NR4A homodimers bind to NurRE, while NR4A:RXR heterodimers bind to DR5 response elements. (b) Additionally, Nurr1 monomers directly interact with p65 on the NFκB RE upon sumoylation and recruit the CoREST corepressor complex, which results in suppression of NFκB-regulated pro-inflammatory genes. Abbreviations: CoREST, REST corepressor; DR5, direct repeat spaced by five nucleotides; NBRE, NGFI-B responsive element; NFκB, nuclear factor-κB; NOR-1, neuron derived orphan receptor 1; NurRE, Nur response element; Nurr1, nuclear receptor related-1 protein; RXR, retinoid X receptor.
Another Csn-B (68) derivative with anticancer activity is 1-(3,4,5-trihydroxyphenyl)nonan-1-one (THPN, 71).(354) A cocrystal structure (pdb 4JGV) revealed binding to the Nur77 LBD surface between helices 5, 7, 8, 9, and 10 (Figure 3d, teal site), where also the close analogue 1-(3,5-dimethoxyphenyl)decan-1-one (DPDO, pdb 4KZI) bound but without protruding toward the subpocket between helices 5 and 7. THPN (71) induced a mitochondrial signaling pathway toward autophagic cell death and was, hence, characterized in cell viability tests in several melanoma and non-melanoma cancer cell lines, in binding studies and in knockdown experiments, while Nur77 transactivation has not been studied. A small SAR evaluation with six THPN (71) derivatives differing in chain length and hydroxyl group substitution pattern revealed a correlation between LBD binding affinity and potency, and resulted in an optimized descendant with C9 instead of C8.(355)
The pentacyclic triterpene celastrol (72) was discovered in a screening of anti-inflammatory natural products in an SPR assay for Nur77 binding where it exhibited a Kd value of 0.29 μM.(356) Binding was confirmed by CD and HPLC analysis, and celastrol (72) reduced transcriptional activity of Nur77 in a reporter gene assay at 0.5 μM in HEK293T cells. Mechanistic investigation revealed enhanced Nur77 mitochondrial translocation to inhibit inflammation via autophagy by direct interaction with a LxxLL motif of TNF receptor-associated factor 2 (TRAF2). Molecular docking studies suggested a similar binding site for celastrol (72) as shown for THPN (71). Isoalantolactone (73) was derived from a natural-product-based small molecule library screen as another Nur77-modulating compound.(357) Two different reporter gene assays in human pancreatic MiaPaCa2 cells and murine 3T3-L1 preadipocytes revealed inverse Nur77 agonism of isoalantolactone (73). By additionally activating AMPKα, the compound exhibited a dual mechanism which collectively inhibited adipogenesis in vitro and in vivo. However, direct interaction of isoalantolactone (73) with Nur77 and its binding site remain elusive.
Early findings on potential endogenous Nur77 ligands were reported by Vinayavekhin et al.(358) who discovered unsaturated fatty acids, namely, arachidonic acid and DHA (45), as Nur77 binders in a metabolomics approach from brain and testes samples. Evidence for binding was reported from an 8-anilino-1-naphthalenesulfonic acid (ANS) displacement assay and from CD experiments with the His6-Nur77 LBD. Prostaglandin A2 (PGA2, 92)(359) was later identified as another potential endogenous agonist for Nur77, and addition of biotinylated PGA2 (92) to recombinant Nur77 protein revealed binding with a Kd value of 2.05 μM according to Western blot analysis and an SPR assay. Covalent interaction of PGA2 (92) with Cys566 was postulated based on covalent molecular docking and molecular dynamic simulation based on the observation that only PGs with an endocyclic Cβ electrophile bound to Nur77. A full-length Nur77 reporter gene assay with a NurRE response element in human bronchial epithelial NHBE cells revealed dose-dependent activity with up to 15-fold Nur77 transactivation at 10 μM PGA2 (92). In line with this, we have recently discovered NSAIDs as Nur77 and NOR-1 modulators with meclofenamic acid (85) acting as Nur77 agonist, and meloxicam, lornoxicam, mofezolac, oxaprozin (83), and parecoxib (84) as inverse Nur77 agonists in a Gal4-Nur77 hybrid reporter gene assay in HEK293T cells.(360) In addition, amodiaquine (AQ, 75) and chloroquine (CQ, 76), initially characterized as Nurr1 modulators, revealed Nur77 and NOR-1 agonism in the same setting. These findings of similar ligand activities on Nur77, Nurr1, and NOR-1 suggest that obtaining selective ligands for the individual NR4A receptors will be challenging.
The antimetabolite 6-mercaptopurine (6-MP, 91), a well-known anticancer agent, was extensively studied as a Nurr1(361) and NOR-1(362) agonist and found to modulate the receptors through the AF-1 region. Nur77 activation by 6-MP (91) is hence thought to follow a similar mechanism. 6-MP (91) strongly activated Nur77 in a full-length reporter gene assay using a homodimer responsive reporter construct in C2C12 murine myoblast cells.(362) However, this activity was accompanied by an induction of Nur77 and other NR4A protein levels suggesting nonspecific effects of 6-MP (91).(363) Fangchinoline,(364) a bisbenzyltetrahydroisoquinoline alkaloid from Stephania tetrandra, modulated Nur77 through the N-terminal region, too, and inhibited Nur77 transactivation in MiaPaCa-2 cells. The natural product exhibited anticancer activity in part via inducing Nur77-dependent pro-apoptotic pathways, whereas no translocation from the nucleus occurred.
Nur77 modulation by the compound series of 1,1-bis(3′-indolyl)-1-(p-phenyl)methane (C-DIM) and analogues is controversial.(365−367) Activating (DIM-C-pPhOCH3, C-DIM5)(367) and inhibiting (DIM-C-pPhOH, C-DIM8)(366) compounds have been reported from this series and were investigated in various types of cancer cell lines. The compounds exhibited Nur77-independent apoptosis induction, kinase induction, and endoplasmic reticulum stress activation, but conclusive evidence for direct modulation of NR4A receptors is missing. The authors of C-DIM characterization as putative NR4A ligands conclude that the modulating activity on Nur77 may be due to indirect activation or deactivation rather than ligand binding.(367) Despite some evidence for direct binding from pull-down assays and CD spectroscopy, no IC50 or EC50 values for C-DIM and analogues are available, and their effects vary significantly depending on the cell context.(365) Effects of C-DIM and analogues reported from animal models are hence difficult to interpret and cannot be related to a clear mode-of-action.
Three further compounds have been reported in the context of Nur77 which do not directly bind to or interact with Nur77 but affect its activity by other mechanisms. 1,3,7-Trihydroxy-2,4-diprenylxanthone (CCE9)(368) and the anticancer agent cisplatin(369) were found to induce Nur77 protein expression, which may have similar effects as Nur77 activation owing to the high constitutive transcriptional activity of Nur77. Z-ligustilide,(370) a phthalide compound from Radix Angelica sinensis, is characterized as an autophagy inhibitor that restored Nur77 from selective degradation by autophagy, thereby enabling Nur77–Ku80 interaction which suppressed double-strand break repair. As a consequence, cell sensitivity to tamoxifen was enhanced in an autophagy-associated fashion.
2.7.1.6. Conclusion
The orphan nuclear receptor Nur77 is an emerging target in several indications including neurodegenerative diseases (summarized in Table 7). Despite ubiquitous expression as well as pleiotropic and nontranscriptional effects, a role of Nur77 in neuroinflammation and dopamine neurotransmission is well described. Validation of Nur77 as a therapeutic target will require multiple further studies, however, which are hindered by the lack of high-quality tool compounds. The unclear mode-of-action, lacking proof for direct interaction, and poor selectivity of C-DIM-based Nur77 modulators compromises the significance of several studies on Nur77 in neurodegeneration. Selective Nur77 agonists and inverse agonists with confirmed direct binding are needed for a deeper understanding of Nur77 in neurodegeneration. Future studies should also further analyze the nongenomic effects involving translocation of Nur77 and whether this pathway can be selectively modulated with ligands.
Table 7. Summarized Observations on Nur77 in Neurodegeneration
| Nur77 (= NR4A1; also known as NGFI-B, TR3, NAK-1, and N10) | |
|---|---|
| Nur77 in AD | Alpha 1-antichymotrypsin/serpinA3 is involved in AD development and Nur77 regulated.(348) |
| Translocation of Nur77-RXR to mitochondria in neurons upon Aβ/H2O2 treatment results in apoptosis.(349) Activation with the RXR agonist 9-RA (43) prevented translocation, reduced apoptosis, and enhanced Bcl-2 expression in vitro and in vivo.(349) | |
| Nur77 in PD | Nur77 knockout slightly enhanced basal locomotor activity in mice and rats.(334,335) |
| Nur77 knockout in mice: TH ↑, dopamine metabolite DOPAC ↑, COMT ↓.(334) | |
| Nur77 knockout in the MPTP PD model had conflicting results: sensitization to dopaminergic cell death(340) and decreased dopaminergic neuronal loss after perturbation.(335) | |
| Nur77 knockout in the 6-OHDA PD model decreased dopaminergic neuronal loss in rats.(335) | |
| Nur77 was downregulated in MPTP in monkeys and in the nigrostriatal region of mice.(339,340) | |
| 6-OHDA treatment induced Nur77 expression in vitro(342) and in vivo.(335) Nurr1 was counter-regulated. | |
| Microglial activation by LPS treatment reduced Nur77 expression in vitro and in vivo (MPTP model).(344) | |
| Nur77 activation (Csn-B (68) or C-DIM5) suppressed NFκB activity in BV2 microglia and counteracted inflammation in vitro.(343−345) | |
| Nur77 in MS | Nur77 knockout enhanced T cells activation and T cell-mediated CNS autoimmunity in vitro and in vivo.(346) |
| Nur77 knockout in EAE caused earlier disease onset and increased EAE score/severity.(346) | |
| Nur77 activation (Csn-B (68)) ameliorated EAE progression and protected from demyelination in wild-type mice but not in Nur77 knockout animals.(347) | |
2.7.2. Nurr1 (NR4A2)
2.7.2.1. Overview
The orphan nuclear receptor related 1 (Nurr1) is the second member of the NR4A subfamily and was initially considered as a ligand-independent transcription factor. The first crystal structure (pdb 1OVL) of the NR4A family in 2003 revealed Nurr1 in apo form in an autoactivated conformation and lacking a canonical ligand binding site due to tightly packed bulky hydrophobic residues within the LBD core(317) (compare Figure 3c). Moreover, structural analysis identified a hydrophobic coregulator interaction surface between helices 11 and 12 distinct from the canonical nuclear receptor coactivator interaction site, which in turn is a highly polar area in the Nurr1 LBD.(371,372) These early findings indicated different regulatory mechanisms and a potentially different coregulatory network for Nurr1. In line with this, we observed ligand-dependent displacement of four coregulator peptides by inverse Nurr1 agonists, namely, NCoR-1 and SMRT, considered as corepressors, the coactivator NCoA6 and the coregulator NRIP1.(360) Additionally, the SUMO-E3 ligase PIASγ is known as a potent repressor of Nurr1 transactivation.(373) Like its relative Nur77 (see section 2.7.1), Nurr1 can act as a monomer (on the NBRE), a homodimer (on the NurRE), and a heterodimer with RXR (on the DR5) on different response elements(319−321) (Figure 4a). Nurr1 is the most extensively studied NR4A member in the context of neurodegenerative diseases. It is mainly expressed in the central nervous system with particularly high abundance in mesencephalic dopaminergic neurons of the ventral tegmental area and substantia nigra pars compacta, and the paraventricular thalamic nuclei.(322) As a key regulator in dopaminergic neuron development and maintenance, Nurr1 is expressed in the midbrain from early prenatal state to adulthood.(374) Nurr1 regulates genes that are essential factors in dopamine neurotransmission such as tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and aromatic l-amino acid decarboxylase (AADC).(374−377) Various Nurr1-regulated genes were discovered in dopaminergic neurons including Dlk1, Ptpru, and Klhl1,(378) the GTP cyclohydrolase,(379) vasoactive intestinal peptide (VIP),(380) receptor tyrosine kinase Ret(381) critical in neurotrophic factor signaling, and topoisomerase IIβ,(382) but also osteopontin, osteocalcin, and neuropilin(29) are Nurr1-dependent. Although Nurr1 is considered as a contributing factor in attention-deficit hyperactivity disorder,(383) inflammatory arthritis,(384) metabolic disease, and cancer (reviewed in ref (385)), emerging evidence ascribes Nurr1 a particularly important role in the pathogenesis of neurodegenerative diseases and presents as a very promising drug target especially in PD.
2.7.2.2. Nurr1 in Parkinson’s Disease
The key regulatory role of Nurr1 in dopaminergic neuron development became apparent in knockout studies, as homozygous Nurr1 knockout mice exhibited a complete loss of ventral mesencephalic dopaminergic neurons, altered gene expression in the dorsal motor nucleus of the brainstem, respiratory dysfunction, and notable hypoactivity, and died within two days after birth.(29,374) Moreover, a number of Nurr1 SNPs were found in patients with familial PD.(29,386) Most notably, the polymorphism rs35479735 located in intron 6 of the Nurr1 gene, which may affect the splicing process, strongly correlates with an increased risk of sporadic and familial PD.(387) Post-mortem analysis of PD patients revealed a significant decrease of Nurr1 expression in nigral neurons containing α-synuclein inclusions, which correlated with loss of TH+ neurons.(388) Accordingly, diminished levels of Nurr1 were also found in nigral dopaminergic rat neurons caused by elevated α-synuclein levels(389) and in MPTP-treated mice.(390) In contrast, Nurr1 overexpression protected dopaminergic neurons against several toxic insults in vitro and in vivo, which was apparent from upregulation of neuroprotective genes and increased neuronal survival.(389−392) Moreover, transplantation of mesenchymal stem cells with lentiviral Nurr1 overexpression in 6-OHDA-treated rats increased the number of TH+ neurons, lowered microglial activation, and reduced expression of inflammatory mediators in the substantia nigra.(393) In microglia and astrocytes, Nurr1 acted as a negative regulator of NFκB-regulated inflammatory genes by stabilizing the CoREST corepressor complex at p65/p50 cis-acting promoter elements(394) (Figure 4b) and thereby limited the production of neurotoxic mediators like TNFα, IL-1β, and iNOS in the substantia nigra of LPS-injected mice. In contrast, interaction of Nurr1 and coactivator Foxa2 in midbrain dopaminergic neurons was found to diminish the Nurr1–CoREST interaction and to induce dopamine phenotype gene expression.(395)
Despite the early assumption that Nurr1 is ligand independent, the antimalarial amodiaquine (AQ, 75) was discovered as an activator of Nurr1 and enhanced the expression of Nurr1-regulated genes (TH, DAT, VMAT2, AADC) in rat NSCs. Moreover, AQ (75) suppressed pro-inflammatory cytokine release after LPS treatment in primary rat microglia and improved behavioral deficits in 6-OHDA-lesioned rats.(396) In addition to AQ (75), the prostaglandins A1 (PGA1, 81) and E1(397) as well as the dopamine metabolite 5,6-dihydroxyindole (DHI, 82)(398) were identified as potential endogenous Nurr1 activators. PGA1 (81) and PGE1 exhibited neuroprotective effects in a primary midbrain dopaminergic neuron-glia coculture derived from rat embryos treated with MPTP or LPS, induced dopaminergic gene expression in MN9D cells in a Nurr1-dependent manner, and attenuated motor deficits in MPTP-induced PD in mice.(397) DHI (82) significantly increased mRNA expression of Nurr1-regulated genes (TH, VMAT2, and DAT) in wild-type zebrafish larvae.(398) The synthetic Nurr1 agonists SA00025 (79)(399) and IP7e (80)(400) also exhibited neuroprotective and anti-inflammatory effects in different rodent PD models. However, Nurr1 levels in the brain were also increased upon treatment with IP7e (80)(400) pointing to other mechanisms than direct Nurr1 activation.
Exploration of Nurr1–RXR heterodimer-specific RXR agonists has further validated Nurr1 activation as a valuable approach to counteract neuroinflammation and PD in vitro and in vivo. XTC0139508 (85),(401) its descendant BRF110 (86),(402) and IRX4204 (90)(403) were intensively studied in vitro for their neuroprotective effects in various neuronal cell cultures and induced Nurr1-regulated genes. Additionally, BRF110 (86)(402) and IRX4204 (90)(403) improved motor function and reduced dopaminergic neuron loss in 6-OHDA and MPTP rodent models. HX600 (87) exhibited neuroprotective effects, too, by lowering levels of pro-inflammatory mediators in LPS-stimulated primary mouse microglia and by reducing ischemic neuronal damage and impaired motor function in an ischemic stroke model in mice.(404)
2.7.2.3. Nurr1 in Alzheimer’s Disease
Beyond Nurr1’s overall neuroprotective and anti-neuroinflammatory activity, its role in AD remains to be studied in detail (recently reviewed in ref (405)). A number of studies indicates involvement of Nurr1 dysregulation as a contributing factor in the pathogenesis of AD. Two in vitro models of AD using Aβ1–42 fibril-treated cells observed downregulation of Nurr1 protein and mRNA levels in primary rat neurons and in a neuronally differentiated human mesenchymal cell line.(406) In addition, Nurr1 mRNA levels in the hippocampus were reduced in mutant APP transgenic mice as a model of early memory loss in AD.(407) Most notably, post-mortem analysis of AD patients revealed a significant decrease of Nurr1 expression in nigral neurons containing neurofibrillary tangles, which correlated with a loss of TH+ neurons.(388) In line with this, 5XFAD mice displayed Nurr1 coexpression with Aβ accumulation in the subiculum and frontal cortex at early stages, and an age-dependent loss of Nurr1-expressing cells in later stages.(408) Nurr1 knockdown by stereotactic Nurr1-shRNA injection in the subiculum amplified AD pathology in 5XFAD mice, whereas Nurr1 overexpression and Nurr1 activation with the agonist AQ (75) ameliorated AD symptoms with reduced Aβ accumulation, less neurodegeneration, and improved cognitive function.(409)
2.7.2.4. Nurr1 in Multiple Sclerosis
Studies on Nurr1 involvement in the context of MS reported contradictory findings. The Nurr1 activator IP7e (80) caused protective effects in EAE in mice by inhibiting NFκB-mediated inflammation in early disease stage.(410) Accordingly, heterozygous Nurr1 knockout mice exhibited an early EAE disease onset with elevated inflammatory infiltrates in the spinal cord.(411) In contrast, systemic RNAi-mediated Nurr1 knockdown in mice attenuated EAE, which was referred to a potential role of Nurr1 in Th17 cell differentiation via regulation of IL-21 and IL-23R expression.(412) The Nurr1 agonist chloroquine (CQ, 76) activated Treg cell differentiation from naïve murine T cells in a Nurr1-dependent manner and significantly suppressed the progression of inflammatory bowel disease, another autoimmune disease, in a dextran sulfate sodium (DSS)-induced mouse model.(413)
2.7.2.5. Nurr1 Ligands and Modulators
Although Nurr1 is considered as an orphan nuclear receptor and lacking a classical ligand-binding site, recent findings of potential endogenous ligands, evidence from cocrystal structures, and mechanistic studies revealed Nurr1 as a promising drug target. In 2015, Kim et al.(396) demonstrated that Nurr1 can be directly modulated via its LBD by small molecules and discovered the two antimalarial drugs AQ (75) and CQ (76) as Nurr1 ligands in a drug screening in a full-length Nurr1 reporter gene assay using a monomer responsive reporter construct in human neuroblastoma SK-N-BE(2)C cells (Scheme 8). Both compounds were shown to interact directly with the LBD by NMR perturbation experiments and mutagenesis studies located the interaction site close to the canonical ligand-binding pocket, which was recently confirmed by Munoz-Tello et al.(351) In addition, we have recently discovered the two AQ-derived fragment-sized Nurr1 agonists 77 and 78 which provided new insights in the activation mechanism of Nurr1 by causing recruitment of NCoR-1 and SMRT upon agonist binding.(414) Another noncanonical binding pocket within the Nurr1 LBD was first discovered for the dopamine metabolite DHI (82) which covalently bound to Cys566 in a Nurr1 cocrystal structure (pdb 6DDA) and thereby induced a pocket between helices 4, 11, and 12 involving outward movement of helix 12(398) (compare Figure 3d, orange site). In vitro, DHI (82) stimulated Nurr1 activity in a Gal4-Nurr1 hybrid reporter gene assay in human choriocarcinoma JGE3 cells by 1.6-fold at 100 μM.
Scheme 8
Scheme 8. Nurr1 Modulators Reported in the Literature(360,396−398,418,422)
First evidence for a potential endogenous Nurr1 ligand was reported for the unsaturated fatty acid DHA (45).(415) Solution NMR spectroscopy mapped the putative ligand-binding pocket close to the AQ binding site and recruitment of a PIASγ peptide was found enhanced by DHA (45) binding. Two full-length reporter gene assays using a monomer responsive reporter construct in HEK293T cells and murine dopaminergic MN9D cells showed dose-dependent repression of Nurr1 activity by ∼25% at 50 μM DHA (45). Further structural analysis by NMR experiments, deuterium uptake mass spectrometry, and molecular dynamic simulations suggested that the putative canonical ligand-binding pocket is able to expand from its collapsed conformation to harbor the unsaturated fatty acid.(416,417) Rajan et al. added two prostaglandins, namely, PGA1 (81) and PGE1, to the collection of Nurr1’s endogenous ligands(397) and found covalent binding of PGA1 (81) to Cys566 (pdb 5Y41) comparable to the ligand-binding pocket induced by DHI (82) with an even stronger 21° shift of helix 12. PGA1 (81) and PGE1 induced Nurr1 transactivation in two different reporter gene assays, Gal4-Nurr1 and full-length Nurr1, performed in murine dopaminergic MN9D cells and N27-A rat dopaminergic neurons with estimated EC50 values of 5 μM and 3 μM. In line with this, we recently discovered several NSAIDs as Nurr1 modulators.(360) Among them, the first-in-class inverse Nurr1 agonists oxaprozin (83) and parecoxib (84) counteracted intrinsic Nurr1 activity in four different reporter gene assay settings in HEK293T cells. Meclofenamic acid (85, Gal4-Nurr1 EC50 4.7 μM) evolved as a Nurr1 modulator with differential activity on different Nurr1 response elements. The NSAIDs also affected the coregulator interaction profile of Nurr1 with NCoR-1, SMRT, NCoA6, and NRIP as well as the receptor’s dimerization equilibrium in HTRF-based assays. Moreover, NSAIDs and AQ-type ligands exhibited simultaneous Nurr1 modulation with additive effects pointing to the existence of two independent binding sites within the Nurr1 LBD.
In addition to these few orthogonally validated direct Nurr1 modulators, further compounds were reported to affect Nurr1 activity for which confirmation of direct interaction is lacking. The imidazopyridine SA00025 (79)(418) has been reported as a potent and selective Nurr1 agonist based on two luciferase reporter gene assays (Gal4-Nurr1fl (EC50 218 nM)(418) and monomer responsive reporter construct (EC50 0.7 nM)(419)). The compound has favorable ADMET and pharmacokinetic properties(418,420) except for a hErg liability (IC50 1.5 μM) and was found to reach the brain of rats after oral administration where it significantly induced Nurr1-regulated gene expression in the substantia nigra after seven days of daily dosing.(399) Direct binding to Nurr1 was studied for several compounds of the SA00025 (79) series by SPR,(419) but the reported data are incomprehensive, and a direct Nurr1 binding of the lead compound SR24237(418) could not be confirmed.(351)
A benzimidazole-based combinatorial approach to Nurr1 modulators has reported SR10098(421) as one of three hits, and Nurr1 agonists with isoxazolopyridinone scaffold were derived from a high-throughput screening (HTS) campaign(422) with subsequent SAR studies. Both series reached low nanomolar potencies in a reporter gene assay in stably Nurr1-expressing MN9D cells. Among these compounds, IP7e (80, EC50 3.9 nM) showed brain bioavailability in mice(422) and was applied to the EAE(410) and a PD(400) mouse model. Data from a recent NMR structural footprinting analysis puts a direct binding of SR10098, IP7e (80), and analogue SR10658 to the Nurr1 LBD into question, however.(351)
As stated for Nur77 (see section 2.7.1), C-DIM derivatives were also extensively studied as Nurr1 modulators with contradictory results in pancreatic(423) and bladder cancer(424) cells, neuronal cells,(425−427) and glioblastoma cells.(428) Multiple anti-inflammatory and neuroprotective effects were also reported from PD mouse models.(425,427,429) Mechanistic evaluation of NR4A modulation by C-DIM derivatives using various hybrid receptor constructs in reporter gene assays demonstrated that the NH2-terminal domain was sufficient for transactivation.(423) Through N-terminal Nurr1 modulation, C-DIM derivatives may hence exhibit direct effects on Nurr1 for example in NFκB transrepression(429) (Figure 4b), but altered Nurr1 protein levels(426) and indirect mechanisms rather than direct Nurr1 transactivation via its LBD appear to dominate the effects.(351)
In addition, the antimetabolite 6-MP (91) was identified as a Nurr1 activator from an HTS utilizing a full-length reporter gene assay under the control of the homodimer responsive element in CV1 cells.(361) Closer evaluation of Nurr1(361) and NOR-1(362) modulation suggested a noncanonical mechanism of nuclear receptor activation through the N-terminal AF-1 domain not involving interaction with the LBD.
A number of other compounds, mostly chemotherapeutic agents, such as camptothecin,(430) the metabolite 7-ethyl-10-hydroxy-camptothecin of irinotecan, and KU0171309(431) (from HTS) were found to inhibit Nurr1 transactivation. Apart from KU0171309 whose mode of Nurr1 modulation remains elusive, these agents were found to suppress Nurr1 activity via inhibition of the EGFR cascade. Furthermore, neuroprotective agents have been discovered which do not directly modulate Nurr1 activity but were shown to induce Nurr1 expression in vitro and in vivo. Among them were the anti-PD drug pramipexol,(432) for which Nurr1 upregulation was proposed to be mediated via the dopamine D3 receptor, the phosphodiesterase-3 inhibitor cilostazol,(433) and moracenin D,(434) a flavonoid extracted from Mori Cortex radicis.
2.7.2.6. Nurr1-RXR Heterodimer-Specific RXR Ligands
As discussed above, Nurr1 can act as a permissive heterodimer with RXR opening another avenue to Nurr1 modulation via heterodimer activation with RXR agonists. Owing to the multitude of RXR heterodimers and associated effects, heterodimer preferential activity is very desirable in this context. Hence, a number of Nurr1–RXR heterodimer-specific RXR ligands (Scheme 9) have been reported which were shown to promote Nurr1 activity or enhance its function in PD models (outlined above). The aminopyrimidine derivative XCT0135908 (XCT, 85)(435) selectively induced luciferase activity dependent on a Gal4–Nurr1–RXRα heterodimer in CV-1 cells. Its activity was blocked by the RXR antagonist LG1208. However, XCT (85) has low plasma stability and poor brain exposure after intraperitoneal administration, and even intracerebroventricular injection failed to show in vivo activity as the expression of Nurr1 regulated genes in midbrain such as TH was not changed.(402) BRF110 (86),(402) a close analogue of XCT (85), activated a full-length Nurr1-RXRα reporter gene assay utilizing a heterodimer responsive reporter construct in the human dopaminergic neuroblastoma cell line SH-SY5Y with an EC50 value of ∼0.9 μM. Its binding to RXRα is only supported by molecular docking studies, but lentiviral knockdown of Nurr1 demonstrated involvement of Nurr1 in heterodimer activation. Pharmacokinetic properties of BRF110 (86) after intraperitoneal administration in mice were improved compared to 85 with CNS bioavailability and a moderate half-life of 1.5 h in plasma and brain. The dibenzodiazepine RXR ligand HX600 (87) was also found to selectively activate Nurr1- and Nur77-RXR heterodimers in several cellular settings.(436,437) The chiral dihydrobenzofuran 88(438) was designed as a full RXR agonist from a series of conformationally constrained RXR ligands with a slight (3-fold) preference for the Nurr1–RXR heterodimer (pEC50 7.9, 111% efficacy) compared to the RXR homodimer (pEC50 7.6, 85% efficacy) in a bioluminescence resonance energy transfer (BRET) assay. Cocrystal structure analysis of RXRα in complex with dihydrobenzofuran 88 and the TIF2 coactivator peptide (pdb 5EC9) confirmed orthosteric binding to RXR and a typical agonist conformation. The synthetic honokiol derivative 89 with a biaryl scaffold demonstrated a greater 25-fold selectivity for the Nurr1-RXRα heterodimer (pEC50 9.1, 129% efficacy) compared to the RXRα homodimer (pEC50 7.7, 291% efficacy) determined in a BRET assay.(439) The respective cocrystal structure analysis indicated that compact ligands, allowing movement of helix 7 and 11, favor RXRα heterodimerization with Nurr1 (pdb 5MKU), whereas ligands with substituents in the 2′ position on the biaryl scaffold induced pocket expansion with helix 12 movement, resulting in lower binding affinity or antagonistic behavior (pdb 5MKJ) and promoting RXRα homodimerization.
Scheme 9
Scheme 9. Nurr1-RXR Heterodimer-Specific RXR Agonists Reported in the Literature(402,403,435,436,438,439)
The RXR ligand IRX4204 (90) has been studied most extensively in the context of neurodegeneration. Profiling of IRX4204 (90) demonstrated potent induction of Nurr1-dependent transcriptional activity (EC50 < 1 nM) in COS7 cells transfected with full-length Nurr1 and RXRα constructs and, surprisingly, a monomer responsive (NBRE) reporter construct.(403) Pharmacokinetic parameters (determined in rats) of IRX4204 (90) were favorable with bioavailability in the brain at reasonable concentrations (11.5 ± 2.9 nM) after oral administration of IRX4204 (90), which was sufficient to induce Nurr1-regulated gene expression in the substantia nigra. In addition to IRX4204 (90), also the most widely used RXR agonist bexarotene (42) was found to favor the Nurr1-RXR heterodimer (pEC50 8.3) over the RXR homodimer (pEC50 7.5) in a BRET assay in HEK293T cells.(440) In vivo experiments demonstrated that bexarotene (42) upregulated Nurr1-dependent genes DAT and VMAT2, rescued dopaminergic neuronal loss, and reversed behavioral deficits in 6-OHDA-lesioned rats. However, the neuroprotective effects of bexarotene (42) cannot be ascribed to Nurr1-mediated effects alone as the LXR–RXR and PPAR–RXR heterodimers are also effectively activated by bexarotene (42). Volakakis et al.(391) observed no effect of bexarotene (42) on dopamine neuron loss and motor impairment in 6-OHDA-injected rats but found bexarotene (42) able to restore disrupted Ret expression and neurotrophic GDNF signaling.
2.7.2.7. Conclusion
Nurr1 is an emerging drug target being extensively studied in the context of neurodegenerative diseases (summarized in Table 8) in which it holds enormous potential as a key regulator of dopaminergic neuron function. However, the available Nurr1 modulator tools are of insufficient quality to fully explore the potential of Nurr1 modulation, and the limited quality of (putative) Nurr1 modulators used in preclinical studies weakens the significance of these experiments. More potent, more selective, and particularly better characterized tools are needed for pharmacological validation of Nurr1 in neurodegeneration and other pathologies. Pending further validation of Nurr1 as a therapeutic target, potent and selective Nurr1 agonists may hold remarkable potential as a disease-modifying approach especially in PD.
Table 8. Summarized Observations on Nurr1 in Neurodegeneration
| Nurr1 (= NR4A2; also known as NOT, TINUR, and HZF-3) | |
|---|---|
| Nurr1 in AD | Nurr1 expression in nigral neurons was found diminished in AD patients.(388) |
| Nurr1 mRNA levels in the hippocampus were decreased in APP transgenic mice.(407) | |
| Nurr1 was coexpressed with Aβ accumulation in the subiculum and frontal cortex in early-stage 5XFAD mice.(408) | |
| 5XFAD mice lose Nurr1 expressing cells in an age-dependent fashion.(408) | |
| shRNA-mediated Nurr1 knockdown in the subiculum worsened AD pathology in 5XFAD mice.(409) | |
| Nurr1 overexpression or activation (AQ (78)) improved AD symptoms (Aß ↓, neurodegeneration ↓, cognitive function ↑) in 5XFAD mice.(409) | |
| Nurr1 in PD | Nurr1 knockout caused loss of dopaminergic neuron development and respiratory dysfunction and is lethal.(29,374) |
| Nurr1 expression in nigral neurons was found decreased in PD patients and in rodent models of PD.(388−390) Diminished Nurr1 levels correlated with high α-synuclein levels and loss of TH+ neurons.(388−390) | |
| Nurr1 overexpression protected neurons against toxic insults of α-synuclein in vitro and in rodent PD models.(389−393) | |
| Nurr1 agonists upregulated neuroprotective and dopaminergic genes in vitro and in vivo.(396−398,403,414) | |
| Nurr1 agonists decreased expression of pro-inflammatory cytokines in vitro.(396,397,404) | |
| Nurr1 agonists and heterodimer-specific Nurr1-RXR agonists exhibited neuroprotective effects and improved symptoms in 6-OHDA-induced PD in mice and rats(396,399,401−403) and attenuated motor deficits in MPTP-treated mice.(397,402) | |
| Nurr1 in MS | Heterozygous Nurr1 knockout caused early EAE onset and enhanced inflammatory infiltrates in the spinal cord.(411) |
| Systemic Nurr1 knockdown attenuated EAE via diminished Th17 cell differentiation.(412) | |
| Nurr1 activator IP7e (80) had protective effects in EAE by decreasing NFκB activity.(410) | |
2.7.3. NOR-1 (NR4A3)
2.7.3.1. Overview
The neuron derived orphan receptor 1 (NOR-1, NR4A3) is a very poorly studied NR, whose developmental and physiological functions remain widely elusive.(441) As third member of the NR4A subfamily, it shares many characteristics of the other two members of this family, with the exception that NOR-1 appears not to form heterodimers with RXR in contrast to Nurr1 and Nur77(385) (compare Figure 4a). Similar as for Nur77 and Nurr1, structural analysis of NOR-1 suggested that the receptor lacks an accessible ligand binding pocket. NOR-1 adopts a self-activated conformation in the absence of a ligand to be constitutively active (compare Figure 3c). Its transcriptional activity hence primarily depends on the expression level.(442) NOR-1 mRNA is expressed in many rodent tissues. A notably high abundance was observed in the developing rat brain, whereas NOR-1 levels in the adult brain were lower.(443) NOR-1 is mainly expressed in the cerebral neocortex, hippocampus, amygdala, cerebellum, and dopaminoceptive areas, for example, striatum, nucleus accumbens, olfactory tubercle, and prefrontal and cingular cortices.(443,444) In contrast, NOR-1 mRNA levels in dopaminergic neurons of the midbrain are low.(443) Additionally, NOR-1 is present in the neuronal cytoplasm throughout the brain and spinal cord.(443) Although one study has reported NOR-1 knockout as embryolethal,(385,445) most knowledge on the therapeutic potential of the orphan receptor results from knockout studies.
2.7.3.2. NOR-1 and Neurodegeneration
According to the scarce available knowledge, NOR-1 is involved in inflammation, vascular biology, immunity, and lipid and glucose metabolism, suggesting that dysregulation of NOR-1 could lead to diseases such as obesity, diabetes, cardiovascular disease, and cancer.(442) In addition, some preliminary evidence indicates that NOR-1 might be involved in the pathogenesis of neurodegenerative diseases. NOR-1 was found to play an important role during development of the CNS by mediating neuronal differentiation and maintaining neuronal plasticity in the adult CNS.(441) In mice, NOR-1 knockout led to impaired axonal growth in the hippocampus, postnatal neuronal cell death, and a compact pyramidal cell layer of Ammon’s horn was not formed at CA1 and CA3 in NOR-1–/– mice.(441) This suggests a specific role for NOR-1 in the survival of CA1 pyramidal cells.(441) In addition, an increased liability to limbic seizures as well as a compromised axonal guidance in the dentate gyrus and in the mossy fibers were observed in NOR-1 knockout mice.(443) Further important evidence for an involvement of NOR-1 in neurodegenerative diseases evolves from its accumulation in Lewy bodies of patients with PD and dementia with Lewy bodies (DLB), and in glial and neuronal cytoplasmic inclusions in multiple system atrophy (MSA).(443) Moreover, NOR-1 induced the anti-apoptotic protein cIAP2 in neuronal cells under oxidative stress, hypoxia, and ischemia(446) and was upregulated by the transcription factor cAMP response element binding protein (CREB) which is considered as an important factor for neuronal survival and neuroprotection.(392) CREB-regulated expression of NOR-1 and the other NR4A receptors was detected in neuronal cells, raising the assumption that the NR4A family receptors function as mediators of CREB-induced neuroprotection and neuronal survival.(392,446)
2.7.3.3. NOR-1 Ligands and Modulators
NOR-1 is classified as an orphan nuclear receptor, and no potent ligand for NOR-1 has been discovered so far. Two NOR-1-activating compounds have been reported in the literature, the anti-inflammatory and antineoplastic drug 6-MP (91)(362) and the eicosanoid prostaglandin A2 (PGA2, 92).(447) PGA2 (92) was shown to bind to the NOR-1 LBD and to activate NOR-1-dependent gene transcription at 10 μM concentration.(447) PGA2 (92) activated the full-length NOR-1 in the presence and absence of RXRα, indicating that RXRα was not necessary for its activity, which agrees with the assumed monomeric activity of NOR-1.(447) Furthermore, it was shown that a NOR-1 mutant lacking the LBD was not activated by PGA2 (92).(447) The effect exerted by PGA2 (92) on NOR-1 is rather weak, however. In contrast to PGA2 (92), which likely activates NOR-1 through its LBD, 6-MP (91) required the N-terminal AF-1 domain for NOR-1 activation.(362) More specifically, the region between amino acid residues 1 and 150 mediated the NOR-1 activation by 6-MP (91).(362) In a Gal4-NOR-1-AF-1-assay, 6-MP (91) achieved a strong 113-fold NOR-1 activation at 50 μM in proliferating murine C2C12 myoblasts.(362) The 6-MP analogues 6-mercaptopurine riboside (93) and 6-mercaptopurine deoxyriboside (94) also activated the N-terminal NOR-1 region.(362)
2.7.3.4. Conclusion
NOR-1 is a very poorly studied orphan nuclear receptor, and little is known about its therapeutic potential (summarized in Table 9). Knockout studies provide preliminary evidence that NOR-1 is involved in neuronal cell survival and might therefore be an attractive target in neurodegenerative diseases. Particularly, the observed accumulation of NOR-1 in Lewy bodies of PD patients and in neuronal cytoplasmic inclusions in MSA as well as its function as a mediator of CREB-induced neuroprotection support this assumption. However, only observations on decreased NOR-1 activity (knockout) are available so far since potent and selective NOR-1 activators are lacking. NOR-1 agonist and inverse agonist tools are urgently required to capture the orphan receptor’s potential in neurodegenerative diseases.
Scheme 10
Scheme 10. NOR-1 Activating Compounds
Table 9. Summarized Observations on NOR-1 in Neurodegeneration
| NOR-1 (= NR4A3; also known as TEC, MINOR, and CHN) | |
|---|---|
| NOR-1 in neurodegeneration | NOR-1 knockout in mice(441) impaired axonal growth in hippocampus, caused postnatal neuronal cell death, and compromised axonal guidance in dentate gyrus and mossy fibers. |
| NOR-1 expression is enhanced by the stress-induced transcription factor CREB, which is an important factor for neuronal survival and neuroprotection.(392,446) | |
2.8. Estrogen receptors (ER, NR3A)
2.8.1. Overview
Estrogen receptors (ER)(448−450) comprise two subtypes ERα and ERβ (ERα, NR3A1; ERβ, NR3A2), which together with the G protein coupled estrogen receptor GPER mediate the effects of estrogens and estrogenic compounds. Although estrogens are primarily female hormones, ERs are crucial transcription factors not only in females but have relevance also in males as illustrated by the infertility of male ERα knockout mice.(449−451) With ER agonists as part of contraceptives and ER antagonists as well as the selective ER modulators (SERMs) as anticancer drugs, ERs have considerable relevance as drug targets.(448,449) ERs are found in female reproductive organs, as well as in bone, brain, liver, colon, skin, and salivary gland with different subtype distributions.(448,449) Although ERα and ERβ share high structural similarity, selective targeting has been achieved with synthetic ligands.(448,449) As steroid receptors, ERs act as homodimers on their response element ERE (GGTCAnnnTGACC) but also exhibit other mechanisms of activity including indirect interaction with the DNA via binding to other transcription factors (“tethering”) as well as rapid nongenomic effects.(448−450) The fact that several neurodegenerative and neuroinflammatory diseases (e.g., MS, AD) have a higher incidence in women(452,453) may suggest an involvement of sexual hormones in their pathogenesis and point to a potential role of ERsas pharmacological targets in neurodegeneration. Mainly based on epidemiological observations, postmenopausal decline in estrogen levels is hypothesized as a potential link to higher prevalence of AD in women.(452,454) Additionally, evidence for an association between ER variants and AD has been reported.(455) ER modulation, therefore, is considered as promising therapeutic strategy particularly in age-related neurodegenerative diseases.(454)
2.8.2. ER in Alzheimer’s Disease
The mechanisms by which estrogens contribute neuroprotective, anti-neuroinflammatory, and anti-neurodegenerative effects are multifaceted. In vitro, estrogens protected cultured neurons against several toxic insults including oxidative stress, excitotoxicity, and Aβ-mediated toxicity.(456−461) These effects were shown to be at least in part dependent on ER activation(459,462,463) and to involve ER-mediated induction of Bcl-2 proteins(464) that promote cell survival. Neuroprotective effects were individually demonstrated for both ER subtypes. In cultured rat cortical neurons, selective ERβ activation was sufficient for neuroprotective effects against Aβ,(465) while in SH-SY5Y neuroblastoma cells, ERα activation protected against Aβ toxicity also in the absence of ERβ.(466) Estrogens also exhibited neuroprotective effects in several rodent models of neurotoxicity,(459,467−470) which could be linked to ER activation.(459) While some observations point to a more prominent role of ERα in neuroprotection,(471,472) activation of both ER subtypes exhibited similar neuroprotective effects in several studies, and their individual contributions have not been elucidated.(473−475) The signaling pathways of ERα- and ERβ-mediated neuroprotection seem to differ,(454,466,472,473,476−478) however, suggesting potentially additive effects for activation of both isoforms. Additionally, extranuclear mechanisms of ERs have been reported to involve in neuroprotection(479) among which mitochondrial activities of ERβ seem to be of particular importance.(480) Estrogens were also found to decrease Aβ formation and to promote its clearance in several studies,(481−487) whereas estrogen deficiency in the brain enhanced plaque formation in a transgenic AD mouse model.(488) Estrogen effects on Aβ levels likely involve ER-mediated upregulation of degrading enzymes (insulin-degrading enzyme and neprilysin),(454,489) but experimental observations also indicate participation of rapid, nongenomic mechanisms.(481−486) A recent in vitro study(490) has shown that ERβ activation with diethylpropionitrile or ERβ overexpression can promote autophagy of extracellular Aβ, while ERβ silencing had the opposite effect.
2.8.3. ER in Parkinson’s Disease
In the context of PD, which in contrast to AD and MS has a higher prevalence in men,(491) effects of estrogen use are controversial,(492−495) and clinical trials(496,497) have failed to demonstrate pronounced therapeutic efficacy of estrogens despite the broad evidence for neuroprotective activity of ER activation in other pathologies. Preclinical studies observed sex differences in estrogen effects in rodent PD models and varying efficacy depending on the treatment start, suggesting that the response to estrogens in the brain is lost over time and that estrogen therapy may have protective effects only when applied during early menopause.(495) Alterations in brain ER levels might hence affect treatment outcomes.(495) Use of ER agonists or SERMs in most rodent PD models was not associated with therapeutic effects,(495,498−500) and only few studies have reported beneficial activities of ER modulation in PD. In 6-OHDA-induced disease in rats, AC-186 (95), a selective ERβ agonist counteracted the loss of dopaminergic neurons in the substantia nigra, cognitive impairment, and motor deficits.(501) Interestingly, AC-186 (95) was superior to 17β-estradiol (96), suggesting an advantage of ERβ selectivity, and the beneficial effects were only present in male animals. Baraka et al.(500) applied different types of ER ligands to 6-OHDA-induced PD in rats. They report therapeutic effects as determined by behavioral observations and biochemical parameters for 17β-estradiol (96), the selective ERα agonists propylpyrazoletriol (PPT, 97), and the SERM raloxifene (98), while the ERβ selective agonist diarylpropionitrile (DPN, 105) and tamoxifen (99) were not active. Overall, strong evidence for ERs as promising targets for PD is lacking.
2.8.4. ER in Neuroinflammation and Multiple Sclerosis
Estrogens also exhibit pronounced anti-neuroinflammatory activity which is mainly attributed to their effects on astrocytes and microglial cells.(453,502−505) ER agonists suppressed the release of pro-inflammatory cytokines after LPS stimulation from primary human astrocyte cultures(506) and inhibited LPS-induced astrocyte activation in rats.(507) Effects of estrogens and ER agonists have hence been broadly studied in the context of MS. Estrogen treatment was effective in several studies in the EAE model of MS in mice(508−511) and downregulated pro-inflammatory cytokine production.(509) Therein, also treatment after disease onset was sufficient to reduce severity.(512) Tiwari-Woodruff et al.(476) observed differences of ERα and ERβ activation in EAE. ERα agonist treatment reduced severity of the disease from onset on, while ERβ agonist treatment had no effect in the early disease stage. At a later stage, ERβ activation caused a pronounced protective effect, however, as observed by faster recovery. ERβ knockout abolished this effect. ERα agonist treatment modulated cytokine levels toward an anti-inflammatory profile, suggesting a systemic immune-modulatory effect, whereas ERβ agonist treatment did not alter cytokine levels compared to vehicle. Both types of selective ER ligands reduced demyelination and axonal loss. Overall, these observations suggest beneficial effects of ER signaling for both subtypes(511,513) in neurodegeneration with a stronger anti-neuroinflammatory component for ERα and more pronounced neuroprotective activity for ERβ. The promising observations on estrogen actions in MS have also led to a number of clinical trials(514−517) to study estrogen treatment in female MS patients, which reported some beneficial effects but were not fully consistent. Circulating estrogen levels were found to inversely correlate with the number of active lesions and relapses. Estrogen treatment reduced the size of lesions and the annual number of relapses.
2.8.5. ER Ligands
Regarding medicinal chemistry, ERs are among the most well-studied NRs and the first NRs for which selective modulation has been broadly established with the selective estrogen receptor modulators (SERMs). Estrogens as the endogenous ER ligands are highly active on both isoforms and also have pharmacological relevance as drugs, but their use is limited by severe adverse effects including elevated risk for breast and endometrial cancer, thromboembolisms, and strokes.(518,519) The ligand binding domains of ERα and ERβ display only 59% sequence identity, which would suggest large differences. The ligand binding sites, however, differ in only two lipophilic residues (ERα: Leu384 and Met421 vs ERβ: Met336 and Ile373). In addition to these minor changes, differences in pocket shape and volume provide access to subtype preferential ligands. Advanced structural understanding of ERs and their modulation by ligands has been obtained from extensive cocrystal structure analysis and mechanistic studies,(520−523) which draw specific pharmacophore models and allow the design of subtype preferential modulators exhibiting agonism or antagonism on the ERs.(519) The two ER subtypes also differ in their expression patterns throughout the body which enables tissue selective ER modulation and can improve safety.(449,524) Because of their reduced systemic adverse effects, selective ERβ agonists might hold potential in neurodegenerative diseases. As outlined above, ERβ activation revealed protective effects in EAE models and against Aβ toxicity suggesting beneficial effects in MS and AD, respectively. However, both ERs are expressed in the CNS and are involved in anti-neuroinflammatory or anti-neurodegenerative effects. ERα activation exhibited stronger therapeutic effects in EAE, and several studies suggest different mechanisms for ERα- and ERβ-mediated effects in the CNS. ER subtype preferential ligands and SERMs might, therefore, not be sufficient to establish safe and effective ER modulators for therapeutic application in neurodegenerative diseases.
The large available collection of small molecule ER ligands comprises steroidal and nonsteroidal compounds and agonists, antagonists, and modulators (Scheme 11). The medicinal chemistry of ER ligands has been extensively summarized in several reviews.(519,525,526) The most active natural estrogen 17β-estradiol (96) and its derivative ethinylestradiol (100) as well as diethylstilbestrol (101) are widely used nonselective agonists for ERα and ERβ. Subtype preferential steroidal ER ligands were developed from estradiol by introduction of a γ-lactone over ring D (102, ERα preference) and a vinyl substituent in 8β-position (103, ERβ preference).(519) Medicinal chemistry efforts have also yielded several chemotypes of nonsteroidal subtype preferential ER agonists such as propylpyrazoletriol (97, PPT, ERα preference),(527) the rigid stilbene analogue 104 (ERα preference),(528) diarylpropionitrile (105, DPN, ERβ preference),(529) FERb033 (106, ERβ preference),(530) prinaberel and its descendant WAY200070 (107, ERβ preference),(531) and AC-186 (95, ERβ preference).(501) Activity in the CNS has been demonstrated for example for ERβ agonist DPN (105) in EAE(476) and for ERβ agonist AC-186 (95) in 6-OHDA-induced PD in rats,(501) suggesting them as preferable tools to further probe ERs in neurodegeneration. A key innovation in targeting ERs were the SERMs(532,533) tamoxifen (99), raloxifene (98),(527,534) bazedoxifene (108), and lasofoxifene (109),(535) which exhibit specific activity profiles on the ER subtypes in different tissues. Owing to the bulky residues added to the ER ligand pharmacophore, SERMs antagonize ER activity by preventing the binding of the activation function in helix H12 to the core of the ER LBD. In the resulting antagonist conformation, the ER LBD exhibits a different coregulator recruitment profile with a preference for corepressor binding.(532,533) Therein, ER modulation by SERMs varies in different tissues, which is rationalized by differential coregulator equipment of different cell types and tissues. They act as ER antagonists in breast tissue, as partial agonists in bone, and activity in endometrium varies depending on the SERM.(532,533) Brain penetration and activation of ER signaling in the CNS were recently demonstrated(536) for the SERM bazedoxifene (108), which could hence serve as an attractive tool to further probe ER modulation in neurodegeneration. Following the SERMs as ER modulatory drugs, the antiestrogen fulvestrant (110)(537) acting as a selective estrogen receptor degrader (SERD) has introduced another strategy to inhibit ER activity, and several further SERDs have been developed(533) of which elacestrant (111)(538) was found to cross the blood–brain barrier(539) suggesting it as a potential tool to study inhibition of ER signaling in the CNS.
Scheme 11
Scheme 11. ER Ligands
2.8.6. Conclusion
While evidence for a role of ER in PD is rather weak, the higher incidence of AD and MS in women and observations from multiple preclinical studies indicate a therapeutic potential of ER modulation in these neurodegenerative pathologies (summarized in Table 10). However, clinical trials have mostly failed to translate the beneficial effects from animal models to patients so far. Varying levels of circulating hormones in the patient cohorts might be an important factor for these failures and suggest that certain patient subgroups might benefit from ER modulation in neurodegeneration. The multitude of estrogen activities and potential adverse effects of ER activation must be considered as a potential limiting factor for ER agonist use in neurodegeneration. Selective targeting of ER in the brain might be an avenue to overcome such obstacles, but whether ER activation in the CNS is sufficient for the beneficial effects in neurodegeneration or whether peripheral effects are contributing remains elusive.
Table 10. Summarized Observations on ER in Neurodegeneration
| ERα (= NR3A1; also known as ESR1) and ERβ (= NR3A2; also known as ESR2 and Erb) | |
|---|---|
| ER in AD | AD prevalence is higher in women than in men.(452) |
| ER activation protected against oxidative stress, excitotoxicity, and Aβ-mediated toxicity in cultured neurons(459,462,463) and in rodent models of neurotoxicity.(459,467−470) | |
| ER activation decreased Aβ formation and promoted its clearance in vivo.(481−487) | |
| Estrogen deficiency in the brain enhanced plaque formation in transgenic AD mice.(488) | |
| ER in PD | PD prevalence is higher in men than in women.(491) |
| No therapeutic benefit of ER activation in clinical trials(496,497) | |
| ERβ activation counteracted loss of dopaminergic neurons, cognitive impairment, and motor deficits in 6-OHDA induced PD in rats.(501) | |
| ER in MS | MS prevalence is higher in women than in men.(453) |
| ER activation suppressed the inflammatory response of astrocytes in vitro(506) and in vivo.(507) | |
| ER activation ameliorated EAE and downregulated pro-inflammatory cytokine release.(508−511) | |
| ERα activation reduced EAE severity from onset on; ERβ activation improved recovery from EAE at a later stage.(476) | |
| Clinical trials on ER activation in female MS patients reported some beneficial but inconsistent outcomes.(514−517) | |
3. Summary and Perspectives
ARTICLE SECTIONS
The NR superfamily with its 48 ligand-activated transcription factors in human presents as a very attractive panel of potential therapeutic targets. Owing to the pronounced and durable effects that modulation of NRs exhibits on gene expression and hence on cellular phenotypes, it appears particularly suitable in the treatment of chronic diseases. Accordingly, NR ligands are used as drugs in cancer treatment (e.g., RXR, ER, androgen receptor), as potent anti-inflammatory agents (e.g., glucocorticoid receptor), and to counteract metabolic imbalance (e.g., PPAR, farnesoid X receptor). Neurodegenerative diseases such as AD, PD, and MS are chronic pathologies and closely linked to chronic inflammation or metabolic imbalance, suggesting a high potential of NR modulation in these diseases, too. Although early evidence for therapeutic effects of NR modulation in neurodegeneration dates back several decades, a major breakthrough has not been achieved, yet, and no NR ligand is used as a drug in such indications. However, preclinical research on NRs as therapeutic targets in neurodegeneration is constantly increasing, and cumulative evidence from pilot clinical trials and cohort studies on polymorphisms or altered NR expression in patients strongly supports the high potential of several NRs as future anti-neurodegenerative and anti-neuroinflammatory targets. The level of evidence for such therapeutic potential, naturally, varies for the different NRs, and most studies in the field have been performed for well-studied proteins such as PPAR and RXR. Nevertheless, recent findings particularly highlight also the orphan receptors Nurr1 and TLX, which are predominantly found in the brain as very promising targets for neurodegenerative disease treatment.
Despite very encouraging preclinical observations and evidence from human patients for the therapeutic potential of several NRs in neurodegeneration, pharmacological validation of these findings is often an obstacle and remains widely incomplete. This is mostly due to a lack of (custom) tool compounds with suitable properties to provide unambiguous data supporting observations from knockout studies or genetic overexpression. Especially the most promising targets such as the orphan receptors Nurr1 and TLX are poorly studied in terms of pharmacological control since potent modulators are not available. It is hence imperative to strengthen ligand discovery and tool compound development efforts for these NRs with the potentially greatest therapeutic promise in neurodegeneration. In addition, the mode-of-action or selectivity of several available tools that have already been used in preclinical models of neurodegeneration is questionable, especially for LXR, revERB, and NR4A receptors, which compromises the significance of studies based on these compounds. Achieving strong selectivity within the protein family may be challenging for some NR ligands, especially within NR families (such as NR4A) but is a key aspect for their proper applicability as pharmacological tools. For example, some evidence points to different roles of LXR subtypes and ER subtypes in the CNS, and recent observations suggest that the NR4A receptors Nur77 and Nurr1 may even have counteracting roles in neuroprotection and neurodegeneration. Such scenarios might also hold true for other closely related NRs, which highlights the importance of selectivity for tool compounds in this context. Some preclinical observations made with nonselective or poorly characterized tools hence cannot be clearly interpreted. Therefore, dedicated (custom) tool compounds to probe the potential of NRs in neurodegeneration are urgently required and must fulfill key criteria such as selectivity and clear mode-of-action but also sufficient BBB penetration.
Another open question often is the desired site/tissue of action for NR modulators to obtain therapeutic effects in neurodegeneration. The RXR agonist bexarotene (42), for example, exhibited some attractive therapeutic effects in vivo, but pharmacokinetic analysis demonstrated very limited CNS exposure suggesting involvement of systemic anti-inflammatory or metabolic effects. For certain widely expressed NRs (RXR, PPAR, LXR, VDR), specific brain targeting may hence not be necessary but should still be studied with suitable CNS penetrant tools to decipher systemic contributions and brain-directed effects of their therapeutic activities. In some cases (e.g., ER, PPAR, LXR), systemic effects might even be the dominant mode-of-action leading to improvements in neurodegenerative pathologies. Therein, adverse effects of systemic actions must also be considered when a long-term modulation of a NR is desired for anti-neurodegenerative activity. In contrast, less distributed NRs with a particularly high abundance in the brain (e.g., Nurr1) or even almost exclusive expression in the brain (e.g., TLX) will require ligands that are able to reach sufficient CNS concentrations which presents as an additional challenge to medicinal chemistry but has, for example, been achieved with dedicated brain-penetrant PPAR agonists. The dominant expression of these NRs in the brain on the other hand might be predictive of lower adverse effects upon their therapeutic modulation since systemic on-target effects are reduced. This may suggest potentially greater safety and hence a greater therapeutic potential for these orphan NRs as targets to treat neurodegeneration.
In summary, ligand-activated transcription factors present as highly attractive molecular targets to counteract neurodegenerative pathologies and thereby hold great promise to address high unmet medical needs in severe health burdens. Despite very promising findings for various nuclear receptors in preclinical models of neurodegeneration, we lack high-quality tool compounds to validate nuclear receptor modulation as a therapeutic strategy. Medicinal chemistry efforts must provide potent, selective, and brain-penetrant pharmacological tools especially for insufficiently studied orphan nuclear receptors to capture the full therapeutic potential of these proteins in neurodegeneration and beyond.
Author Information
ARTICLE SECTIONS
- Daniel Merk - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany;
https://orcid.org/0000-0002-5359-8128;
S.W. and D.Z. contributed equally to this work.
Biographies
ARTICLE SECTIONS
Sabine Willems
Sabine Willems studied Pharmacy at Goethe University Frankfurt between 2012 and 2016 and received her license as a pharmacist in 2017. Currently, she is a Ph.D. student in Medicinal Chemistry at the Institute of Pharmaceutical Chemistry at the Goethe University focusing on the development and characterization of (orphan) nuclear receptor ligands.
Daniel Zaienne
Daniel Zaienne obtained Bachelor and Master of Science degrees in Chemistry from Goethe University Frankfurt in 2017 and in 2019, respectively. He then joined the Institute of Pharmaceutical Chemistry at Goethe University Frankfurt as a Ph.D. student, where he currently focuses on the synthesis and characterization of nuclear receptor ligands.
Daniel Merk
Daniel Merk graduated in Pharmaceutical Sciences and Pharmacy from LMU Munich in 2011 and obtained his Ph.D. in Pharmaceutical and Medicinal Chemistry from Goethe University Frankfurt in 2015. He was a Junior Group Leader in Pharmaceutical Chemistry at Goethe University Frankfurt and Postdoctoral ETH Fellowship Scholar at the Institute of Pharmaceutical Sciences of the Swiss Federal Institute of Technology (ETH) Zurich before he finished his Habilitation in Pharmaceutical Chemistry at Goethe University Frankfurt in 2019. Since then, he has been Independent Group Leader in Pharmaceutical Chemistry at Goethe University Frankfurt focusing on the Medicinal Chemistry and Pharmacology of nuclear receptors and their ligands. Recently, he joined LMU Munich as Chair of Pharmaceutical and Medicinal Chemistry.
| Abbreviations | |
| 6-MP | 6-mercaptopurine |
| 6-OHDA | 6-hydroxy dopamine |
| 9-cis RA | 9-cis retinoic acid |
| AADC | aromatic l-amino acid decarboxylase |
| ABC | ATP-binding cassette transporter |
| AD | Alzheimer’s disease |
| ADMET | absorption, distribution, metabolism, excretion, and toxicity |
| AF | activation function |
| APP | amyloid precursor protein |
| ATP | adenosine triphosphate |
| Aβ | amyloid-β |
| Bcl-2 | B-cell lymphoma 2 |
| BBB | blood–brain barrier |
| BRET | bioluminescence resonance energy transfer |
| CD | circular dichroism |
| C-DIM | 1,1-bis(3′-indolyl)-1-(p-substituted phenyl)-methane derivatives |
| CNS | central nervous system |
| CoREST | REST corepressor |
| COX | cyclooxygenase |
| CREB | cAMP response element binding protein |
| CSF | cerebrospinal fluid |
| DAT | dopamine transporter |
| DBD | DNA binding domain |
| DHA | docosahexaenoic acid |
| DR3/5 | direct repeats spaced by 3/5 nucleotides |
| EAE | experimental autoimmune encephalomyelitis |
| EGFR | epidermal growth factor receptor |
| ER | estrogen receptor |
| fl | full length |
| GDNF | glial cell-derived neurotrophic factor |
| HTS | high-throughput screening |
| IFN | interferon |
| IL | interleukin |
| iNOS | inducible NO-synthase |
| IκBα | inhibitor of NF-κB |
| LBD | ligand binding domain |
| LPS | lipopolysaccharide |
| LXR | liver X receptor |
| MOG | myelin oligodendrocyte glycoprotein |
| MPP+ | 1-methyl-4-phenylpyridinium |
| MPTP | 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine |
| MS | multiple sclerosis |
| NBRE | NGFI-B responsive element |
| NCoR | nuclear receptor corepressor |
| NFκB | nuclear factor-κB |
| NGFI-B | nerve growth factor-induced clone B |
| NMDA | N-methyl-d-aspartate |
| NOR-1 | neuron derived orphan receptor 1 |
| NR | nuclear receptor |
| NRE | nuclear receptor response element |
| NRIP | nuclear receptor-interacting protein |
| NSAIDs | nonsteroidal anti-inflammatory drugs |
| NSC | neural stem cell |
| Nurr1 | nuclear receptor related-1 protein |
| NurRE | Nur response element |
| OL | oligodendrocyte |
| OPC | oligodendrocyte progenitor cells |
| PAINS | pan-assay interference compounds |
| PBMC | peripheral blood mononuclear cell |
| PD | Parkinson’s disease |
| PG | prostaglandin |
| P-gp | P-glycoprotein |
| PHA | phytohemagglutinin |
| PIASγ | protein inhibitor of activated STAT protein gamma |
| POMC | proopiomelanocortin |
| PPAR | peroxisome proliferator-activated receptor |
| PS1 | presenilin 1 |
| RE | response element |
| Ret | receptor tyrosine kinase Ret |
| RevERB | reverse ERB |
| RNAi | RNA interference |
| ROR | retinoic acid receptor related orphan receptors |
| RXR | retinoid X receptor |
| SAR | structure–activity relationship |
| SERM | selective estrogen receptor modulator |
| SMRT | silencing mediator for retinoid or thyroid hormone receptors |
| SNP | single-nucleotide polymorphism |
| SPR | surface plasmon resonance |
| TGF | transforming growth factor |
| Th | T helper cell |
| TH | tyrosine hydroxylase |
| THR | thyroid hormone receptor |
| TLX | tailless homologue |
| TNFα | tumor necrosis factor α |
| Treg | regulatory T cell |
| VDR | vitamin D receptor |
| VMAT2 | vesicular monoamine transporter 2 |
References
ARTICLE SECTIONS
This article references 539 other publications.
- 1Prince, M.; Bryce, R.; Albanese, E.; Wimo, A.; Ribeiro, W.; Ferri, C. P. The Global Prevalence of Dementia: A Systematic Review and Metaanalysis. Alzheimer's Dementia 2013, 9 (1), 63– 75.e2, DOI: 10.1016/j.jalz.2012.11.007[Crossref], [PubMed], [CAS], Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s3osVemsQ%253D%253D&md5=cbf1b2107d191f459ba6fe3e6194b3ecThe global prevalence of dementia: a systematic review and metaanalysisPrince Martin; Bryce Renata; Albanese Emiliano; Wimo Anders; Ribeiro Wagner; Ferri Cleusa PAlzheimer's & dementia : the journal of the Alzheimer's Association (2013), 9 (1), 63-75.e2 ISSN:.BACKGROUND: The evidence base on the prevalence of dementia is expanding rapidly, particularly in countries with low and middle incomes. A reappraisal of global prevalence and numbers is due, given the significant implications for social and public policy and planning. METHODS: In this study we provide a systematic review of the global literature on the prevalence of dementia (1980-2009) and metaanalysis to estimate the prevalence and numbers of those affected, aged ≥60 years in 21 Global Burden of Disease regions. RESULTS: Age-standardized prevalence for those aged ≥60 years varied in a narrow band, 5%-7% in most world regions, with a higher prevalence in Latin America (8.5%), and a distinctively lower prevalence in the four sub-Saharan African regions (2%-4%). It was estimated that 35.6 million people lived with dementia worldwide in 2010, with numbers expected to almost double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050. In 2010, 58% of all people with dementia lived in countries with low or middle incomes, with this proportion anticipated to rise to 63% in 2030 and 71% in 2050. CONCLUSION: The detailed estimates in this study constitute the best current basis for policymaking, planning, and allocation of health and welfare resources in dementia care. The age-specific prevalence of dementia varies little between world regions, and may converge further. Future projections of numbers of people with dementia may be modified substantially by preventive interventions (lowering incidence), improvements in treatment and care (prolonging survival), and disease-modifying interventions (preventing or slowing progression). All countries need to commission nationally representative surveys that are repeated regularly to monitor trends.
- 2Moutinho, M.; Codocedo, J. F.; Puntambekar, S. S.; Landreth, G. E. Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation. Annu. Rev. Pharmacol. Toxicol. 2019, 59, 237– 261[Crossref], [PubMed], [CAS], Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslSktrvJ&md5=f73dcd18cd535d4a8d041e843c11c92dNuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in TranslationMoutinho, Miguel; Codocedo, Juan F.; Puntambekar, Shweta S.; Landreth, Gary E.Annual Review of Pharmacology and Toxicology (2019), 59 (), 237-261CODEN: ARPTDI; ISSN:0362-1642. (Annual Reviews)A review. Neurodegenerative diseases are characterized by a progressive loss of neurons that leads to a broad range of disabilities, including severe cognitive decline and motor impairment, for which there are no effective therapies. Several lines of evidence support a putative therapeutic role of nuclear receptors (NRs) in these types of disorders. NRs are ligand-activated transcription factors that regulate the expression of a wide range of genes linked to metab. and inflammation. Although the activation of NRs in animal models of neurodegenerative disease exhibits promising results, the translation of this strategy to clin. practice has been unsuccessful. In this review we discuss the role of NRs in neurodegenerative diseases in light of preclin. and clin. studies, as well as new findings derived from the anal. of transcriptomic databases from humans and animal models. We discuss the failure in the translation of NR-based therapeutic approaches and consider alternative and novel research avenues in the development of effective therapies for neurodegenerative diseases.
- 3Abraha, I.; Rimland, J. M.; Trotta, F. M.; Dell’Aquila, G.; Cruz-Jentoft, A.; Petrovic, M.; Gudmundsson, A.; Soiza, R.; O’Mahony, D.; Guaita, A.; Cherubini, A. Systematic Review of Systematic Reviews of Non-Pharmacological Interventions to Treat Behavioural Disturbances in Older Patients with Dementia. The SENATOR-OnTop Series. BMJ. Open 2017, 7, e012759, DOI: 10.1136/bmjopen-2016-012759
- 4Schmidt, R.; Hofer, E.; Bouwman, F. H.; Buerger, K.; Cordonnier, C.; Fladby, T.; Galimberti, D.; Georges, J.; Heneka, M. T.; Hort, J.; Laczó, J.; Molinuevo, J. L.; O’Brien, J. T.; Religa, D.; Scheltens, P.; Schott, J. M.; Sorbi, S. EFNS-ENS/EAN Guideline on Concomitant Use of Cholinesterase Inhibitors and Memantine in Moderate to Severe Alzheimer’s Disease. Eur. J. Neurol. 2015, 22 (6), 889– 898, DOI: 10.1111/ene.12707[Crossref], [PubMed], [CAS], Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MnnvVejug%253D%253D&md5=29df2ef367c521b297d5621538032babEFNS-ENS/EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer's diseaseSchmidt R; Hofer E; Bouwman F H; Buerger K; Cordonnier C; Fladby T; Galimberti D; Georges J; Heneka M T; Hort J; Laczo J; Molinuevo J L; O'Brien J T; Religa D; Scheltens P; Schott J M; Sorbi SEuropean journal of neurology (2015), 22 (6), 889-98 ISSN:.BACKGROUND AND PURPOSE: Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer's disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL). METHODS: A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) -0.20; 95% confidence interval (CI) -0.31; -0.09], cognitive functioning (SMD -0.27, 95% CI -0.37; -0.17) and behaviour (SMD -0.19; 95% CI -0.31; -0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak. CONCLUSIONS: We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak.
- 5McShane, R.; Areosa Sastre, A.; Minakaran, N. Memantine for Dementia. Cochrane Database Syst. Rev. 2006, No. 2. DOI: 10.1002/14651858.CD003154.pub5
- 6Birks, J.; Grimley Evans, J. Ginkgo Biloba for Cognitive Impairment and Dementia. Cochrane Database Syst. Rev. 2009, No. 1. DOI: 10.1002/14651858.CD003120.pub3
- 7Masters, C. L.; Bateman, R.; Blennow, K.; Rowe, C. C.; Sperling, R. A.; Cummings, J. L. Alzheimer’s Disease. Nat. Rev. Dis. Prim. 2015, 1 (1), 15056, DOI: 10.1038/nrdp.2015.56
- 8Congdon, E. E.; Sigurdsson, E. M. Tau-Targeting Therapies for Alzheimer Disease. Nat. Rev. Neurol. 2018, 14 (7), 399– 415, DOI: 10.1038/s41582-018-0013-z[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFaks73M&md5=d26350964814206ce4860b7256c9d6a0Tau-targeting therapies for Alzheimer diseaseCongdon, Erin E.; Sigurdsson, Einar M.Nature Reviews Neurology (2018), 14 (7), 399-415CODEN: NRNACP; ISSN:1759-4758. (Nature Research)A review. Alzheimer disease (AD) is the most common form of dementia. Pathol., AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, with assocd. loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles, resp. In the decades since Aβ and tau were identified, development of therapies for AD has primarily focused on Aβ, but tau has received more attention in recent years, in part because of the failure of various Aβ-targeting treatments in clin. trials. In this article, we review the current status of tau-targeting therapies for AD. Initially, potential anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting therapies in clin. trials are immunotherapies, which have shown promise in numerous preclin. studies. Given that tau pathol. correlates better with cognitive impairments than do Aβ lesions, targeting of tau is expected to be more effective than Aβ clearance once the clin. symptoms are evident. With future improvements in diagnostics, these two hallmarks of the disease might be targeted prophylactically.
- 9Panza, F.; Lozupone, M.; Logroscino, G.; Imbimbo, B. P. A Critical Appraisal of Amyloid-β-Targeting Therapies for Alzheimer Disease. Nat. Rev. Neurol. 2019, 15 (2), 73– 88, DOI: 10.1038/s41582-018-0116-6[Crossref], [PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cnotFagtA%253D%253D&md5=fa63b5a3ca7e25169dfd6566f56b5152A critical appraisal of amyloid-β-targeting therapies for Alzheimer diseasePanza Francesco; Lozupone Madia; Logroscino Giancarlo; Panza Francesco; Logroscino Giancarlo; Panza Francesco; Imbimbo Bruno PNature reviews. Neurology (2019), 15 (2), 73-88 ISSN:.Brain accumulation of the amyloid-β (Aβ) peptide is believed to be the initial event in the Alzheimer disease (AD) process. Aβ accumulation begins 15-20 years before clinical symptoms occur, mainly owing to defective brain clearance of the peptide. Over the past 20 years, we have seen intensive efforts to decrease the levels of Aβ monomers, oligomers, aggregates and plaques using compounds that decrease production, antagonize aggregation or increase brain clearance of Aβ. Unfortunately, these approaches have failed to show clinical benefit in large clinical trials involving patients with mild to moderate AD. Clinical trials in patients at earlier stages of the disease are ongoing, but the initial results have not been clinically impressive. Efforts are now being directed against Aβ oligomers, the most neurotoxic molecular species, and monoclonal antibodies directed against these oligomers are producing encouraging results. However, Aβ oligomers are in equilibrium with both monomeric and aggregated species; thus, previous drugs that efficiently removed monomeric Aβ or Aβ plaques should have produced clinical benefits. In patients with sporadic AD, Aβ accumulation could be a reactive compensatory response to neuronal damage of unknown cause, and alternative strategies, including interference with modifiable risk factors, might be needed to defeat this devastating disease.
- 10Uliassi, E.; Gandini, A.; Perone, R. C.; Bolognesi, M. L. Neuroregeneration versus Neurodegeneration: Toward a Paradigm Shift in Alzheimer’s Disease Drug Discovery. Future Med. Chem. 2017, 9 (10), 995– 1013, DOI: 10.4155/fmc-2017-0038[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVCkt7nN&md5=bbbe7af9d8f6b0e7ad76e9c9a2561b5aNeuroregeneration versus neurodegeneration: toward a paradigm shift in Alzheimer's disease drug discoveryUliassi, Elisa; Gandini, Annachiara; Perone, Rosaria Carmela; Bolognesi, Maria LauraFuture Medicinal Chemistry (2017), 9 (10), 995-1013CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)Alzheimer's disease represents an enormous global burden in terms of human suffering and economic cost. To tackle the current lack of effective drugs and the continuous clin. trial failures might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting neural stem cells (NSCs) regeneration. In this context, small mols. have come to the forefront for their potential to manipulate NSCs, provide therapeutic tools and unveil NSCs biol. Classically, these mols. have been generated either by target-based or phenotypic approaches. To circumvent specific liabilities, nanomedicines emerge as a feasible alternative. However, this review is not intended to be comprehensive. Its purpose is to focus on recent examples that could accelerate development of neuroregenerative drugs against Alzheimer's disease.
- 11Wang, J.; Gu, B. J.; Masters, C. L.; Wang, Y.-J. A Systemic View of Alzheimer Disease — Insights from Amyloid-β Metabolism beyond the Brain. Nat. Rev. Neurol. 2017, 13 (10), 612– 623, DOI: 10.1038/nrneurol.2017.111[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFCrsL3F&md5=36954bc3ed9adb7b5c0111f177f02caaA systemic view of Alzheimer disease - insights from amyloid-β metabolism beyond the brainWang, Jun; Gu, Ben J.; Masters, Colin L.; Wang, Yan-JiangNature Reviews Neurology (2017), 13 (10), 612-623CODEN: NRNACP; ISSN:1759-4758. (Nature Research)A review. Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becoming more clearly defined. This Review focuses on amyloid-β (Aβ), a major hallmark of AD. We review emerging findings of assocns. between systemic abnormalities and Aβ metab., and describe how these assocns. might interact with or reflect on the central pathways of Aβ prodn. and clearance. On the basis of these findings, we propose that these abnormal systemic changes might not only develop secondary to brain dysfunction but might also affect AD progression, suggesting that the interactions between the brain and the periphery have a crucial role in the development and progression of AD. Such a systemic view of the mol. pathogenesis of AD could provide a novel perspective for understanding this disease and present new opportunities for its early diagnosis and treatment.
- 12Elkouzi, A.; Vedam-Mai, V.; Eisinger, R. S.; Okun, M. S. Emerging Therapies in Parkinson Disease — Repurposed Drugs and New Approaches. Nat. Rev. Neurol. 2019, 15 (4), 204– 223, DOI: 10.1038/s41582-019-0155-7[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cbjslGhsA%253D%253D&md5=5a3a423ad75f007ee27708cd0e80e6a2Emerging therapies in Parkinson disease - repurposed drugs and new approachesElkouzi Ahmad; Vedam-Mai Vinata; Eisinger Robert S; Okun Michael S; Vedam-Mai Vinata; Okun Michael SNature reviews. Neurology (2019), 15 (4), 204-223 ISSN:.Parkinson disease (PD) treatment options have conventionally focused on dopamine replacement and provision of symptomatic relief. Current treatments cause undesirable adverse effects, and a large unmet clinical need remains for treatments that offer disease modification and that address symptoms resistant to levodopa. Advances in high-throughput drug screening methods for small molecules, developments in disease modelling and improvements in analytical technologies have collectively contributed to the emergence of novel compounds, repurposed drugs and new technologies. In this Review, we focus on disease-modifying and symptomatic therapies under development for PD. We review cellular therapies and repurposed drugs, such as nilotinib, inosine, isradipine, iron chelators and anti-inflammatories, and discuss how their success in preclinical models has paved the way for clinical trials. We provide an update on immunotherapies and vaccines. In addition, we review non-pharmacological interventions targeting motor symptoms, including gene therapy, adaptive deep brain stimulation (DBS) and optogenetically inspired DBS. Given the many clinical phenotypes of PD, individualization of therapy and precision of treatment are likely to become important in the future.
- 13de Lau, L. M. L.; Breteler, M. M. B. Epidemiology of Parkinson’s Disease. Lancet Neurol. 2006, 5 (6), 525– 535, DOI: 10.1016/S1474-4422(06)70471-9[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD283osVehtg%253D%253D&md5=2c22b5eb8ff98db0a23d568123adea4bEpidemiology of Parkinson's diseasede Lau Lonneke M L; Breteler Monique M BThe Lancet. Neurology (2006), 5 (6), 525-35 ISSN:1474-4422.The causes of Parkinson's disease (PD), the second most common neurodegenerative disorder, are still largely unknown. Current thinking is that major gene mutations cause only a small proportion of all cases and that in most cases, non-genetic factors play a part, probably in interaction with susceptibility genes. Numerous epidemiological studies have been done to identify such non-genetic risk factors, but most were small and methodologically limited. Larger, well-designed prospective cohort studies have only recently reached a stage at which they have enough incident patients and person-years of follow-up to investigate possible risk factors and their interactions. In this article, we review what is known about the prevalence, incidence, risk factors, and prognosis of PD from epidemiological studies.
- 14Parkinson’s Disease in Adults. NICE Guidelines, 2017, NG71.
- 15Deuschl, G.; de Bie, R. M. A. New Therapeutic Developments for Parkinson Disease. Nat. Rev. Neurol. 2019, 15 (2), 68– 69, DOI: 10.1038/s41582-019-0133-0[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cjit1Gmug%253D%253D&md5=ccfa10002627723d357d778534ccb8deNew therapeutic developments for Parkinson diseaseDeuschl Gunther; de Bie Rob M ANature reviews. Neurology (2019), 15 (2), 68-69 ISSN:.There is no expanded citation for this reference.
- 16Doshi, A.; Chataway, J. Multiple Sclerosis, a Treatable Disease. Clin. Med. (Northfield. Il). 2016, 16 (6), s53– s59, DOI: 10.7861/clinmedicine.16-6-s53
- 17Tintore, M.; Vidal-Jordana, A.; Sastre-Garriga, J. Treatment of Multiple Sclerosis — Success from Bench to Bedside. Nat. Rev. Neurol. 2019, 15 (1), 53– 58, DOI: 10.1038/s41582-018-0082-z[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvV2qsb3O&md5=5067f9830346fe6e03cafd670e0ecfbbTreatment of multiple sclerosis - success from bench to bedsideTintore, Mar; Vidal-Jordana, Angela; Sastre-Garriga, JaumeNature Reviews Neurology (2019), 15 (1), 53-58CODEN: NRNACP; ISSN:1759-4758. (Nature Research)The modern era of multiple sclerosis (MS) treatment began 25 years ago, with the approval of IFNβ and glatiramer acetate for the treatment of relapsing-remitting MS. Ten years later, the first monoclonal antibody, natalizumab, was approved, followed by a third important landmark with the introduction of oral medications, initially fingolimod and then teriflunomide, di-Me fumarate and cladribine. Concomitantly, new monoclonal antibodies (alemtuzumab and ocrelizumab) have been developed and approved. The modern era of MS therapy reached primary progressive MS in 2018, with the approval of ocrelizumab. We have also learned the importance of starting treatment early and the importance of clin. and MRI monitoring to assess treatment response and safety. Treatment decisions should account for disease phenotype, prognostic factors, comorbidities, the desire for pregnancy and the patient's preferences in terms of acceptable risk. The development of treatment for MS during the past 25 years is a fantastic success of translational medicine.
- 18Stangel, M.; Kuhlmann, T.; Matthews, P. M.; Kilpatrick, T. J. Achievements and Obstacles of Remyelinating Therapies in Multiple Sclerosis. Nat. Rev. Neurol. 2017, 13 (12), 742– 754, DOI: 10.1038/nrneurol.2017.139[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M3itFaktg%253D%253D&md5=bfc226793aced3e8c04ce8b7306bbf20Achievements and obstacles of remyelinating therapies in multiple sclerosisStangel Martin; Kuhlmann Tanja; Matthews Paul M; Kilpatrick Trevor JNature reviews. Neurology (2017), 13 (12), 742-754 ISSN:.Remyelination in the CNS is the natural process of damage repair in demyelinating diseases such as multiple sclerosis (MS). However, remyelination becomes inadequate in many people with MS, which results in axonal degeneration and clinical disability. Enhancement of remyelination is a logical therapeutic goal; nevertheless, all currently licensed therapies for MS are immunomodulatory and do not support remyelination directly. Several molecular pathways have been identified as potential therapeutic targets to induce remyelination, and some of these have now been assessed in proof-of-concept clinical trials. However, trial design faces several obstacles: optimal clinical or paraclinical outcome measures to assess remyelination remain ill-defined, and identification of the ideal timing of therapy is also a crucial issue. In addition, realistic expectations are needed concerning the probable benefits of such therapies. Nevertheless, approaches that enhance remyelination are likely to be protective for axons and so could prevent long-term neurodegeneration. Future MS treatment paradigms, therefore, are likely to comprise a combinatorial approach that involves both immunomodulatory and regenerative treatments.
- 19Zhao, C.; Deng, W.; Gage, F. H. Mechanisms and Functional Implications of Adult Neurogenesis. Cell 2008, 132 (4), 645– 660, DOI: 10.1016/j.cell.2008.01.033[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXivVagtrY%253D&md5=8ab05939596eda4ed9fa77ed242e3c8fMechanisms and functional implications of adult neurogenesisZhao, Chunmei; Deng, Wei; Gage, Fred H.Cell (Cambridge, MA, United States) (2008), 132 (4), 645-660CODEN: CELLB5; ISSN:0092-8674. (Cell Press)A review. The generation of new neurons is sustained throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. We discuss the factors that regulate proliferation and fate detn. of adult neural stem cells and describe recent studies concerning the integration of newborn neurons into the existing neural circuitry. We further address the potential significance of adult neurogenesis in memory, depression, and neurodegenerative disorders such as Alzheimer's and Parkinson's disease.
- 20Germain, P.; Staels, B.; Dacquet, C.; Spedding, M.; Laudet, V. Overview of Nomenclature of Nuclear Receptors. Pharmacol. Rev. 2006, 58 (4), 685– 704, DOI: 10.1124/pr.58.4.2[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1ajtA%253D%253D&md5=264d69bdcd7b9f01f2d6ef3b73b78c60Overview of nomenclature of nuclear receptorsGermain, Pierre; Staels, Bart; Dacquet, Catherine; Spedding, Michael; Laudet, VincentPharmacological Reviews (2006), 58 (4), 685-704CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. Nuclear receptor pharmacol. has, to a certain extent, led the way, compared with other receptor systems, in the appreciation that ligands may exert very diverse pharmacol., based on their individual chem. structure and the allosteric changes induced in the receptor/accessory protein complex. This can lead to very selective pharmacol. effects, which may not necessarily be predicted from the experience with other agonists/partial agonists/antagonists. If this is the case, then drug discovery may be back to drug-specific pharmacol. (where each drug may have an original profile), rather than specific-drug pharmacol. (where agents specific for a receptor have a distinct profile). As functional selectivity is indeed a crucial mechanism to be considered when going through the drug discovery development process, then initial screens using reconstituted systems may not show the appropriate pharmacol., simply because the required stoichiometry of corepressors and coactivators may not be present to select the best compds.; therefore, multiple effector systems are necessary to screen for differential activation, and, even then, screening with in vivo pathophysiol. models may ultimately be required for the selection process-a massive but necessary task for pharmacologists. Thus, the characterization of nuclear receptors and their assocd. proteins and the ligands that interact with them will remain a challenge to pharmacologists.
- 21Aranda, A.; Pascual, A. Nuclear Hormone Receptors and Gene Expression. Physiol. Rev. 2001, 81 (3), 1269– 1304, DOI: 10.1152/physrev.2001.81.3.1269[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlt1Ohsrs%253D&md5=67ea9f6274b2a19bce09dd1c83a5f839Nuclear hormone receptors and gene expressionAranda, Ana; Pascual, AngelPhysiological Reviews (2001), 81 (3), 1269-1304CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)A review, with 324 refs. The nuclear hormone receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as different orphan receptors of unknown ligand. Ligands for some of these receptors have been recently identified, showing that products of lipid metab. such as fatty acids, prostaglandins, or cholesterol derivs. can regulate gene expression by binding to nuclear receptors. Nuclear receptors act as ligand-inducible transcription factors by directly interacting as monomers, homodimers, or heterodimers with the retinoid X receptor with DNA response elements of target genes, as well as by cross-talking to other signaling pathways. The effects of nuclear receptors on transcription are mediated through recruitment of coregulators. A subset of receptors binds corepressor factors and actively represses target gene expression in the absence of ligand. Corepressors are found within multicomponent complexes that contain histone deacetylase activity. Deacetylation leads to chromatin compaction and transcriptional repression. Upon ligand binding the receptors undergo a conformational change that allows the recruitment of multiple coactivator complexes. Some of these proteins are chromatin remodeling factors or possess histone acetylase activity whereas others may interact directly with the basic transcriptional machinery. Recruitment of coactivator complexes to the target promoter causes chromatin decompaction and transcriptional activation. The characterization of corepressor and coactivator complexes, in concert with the identification of the. Specific interaction motifs in the receptors, has demonstrated the existence of a general mol. mechanism by which different receptors elicit their transcriptional responses in target genes.
- 22De Bosscher, K.; Desmet, S. J.; Clarisse, D.; Estébanez-Perpiña, E.; Brunsveld, L. Nuclear Receptor Crosstalk — Defining the Mechanisms for Therapeutic Innovation. Nat. Rev. Endocrinol. 2020, 16 (7), 363– 377, DOI: 10.1038/s41574-020-0349-5[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnsVWltr8%253D&md5=22a5fe52c359ac1757d24fcde6d74a54Nuclear receptor crosstalk - defining the mechanisms for therapeutic innovationDe Bosscher, Karolien; Desmet, Sofie J.; Clarisse, Dorien; Estebanez-Perpina, Eva; Brunsveld, LucNature Reviews Endocrinology (2020), 16 (7), 363-377CODEN: NREABD; ISSN:1759-5029. (Nature Research)A review. Abstr.: Nuclear receptor crosstalk can be defined as the interplay between different nuclear receptors or between their overlapping signaling pathways. A subset of nuclear receptors (such as PPARs and RARs) engage in the formation of well-characterized 'typical' heterodimers with RXR. 'Atypical' heterodimers (such as GR with PPARs, or PPAR with ERR) might form a novel class of phys. complexes that might be more transient in nature. These heterodimers might harbor strong transcriptional flexibility, with no strict need for DNA binding of both partners. Direct crosstalk could stem from a pairwise phys. assocn. between atypical nuclear receptor heterodimers, either via pre-existing interaction pairs or via interactions that are newly induced with small mols.; such crosstalk might constitute an uncharted space to target nuclear receptor physiol. and/or pathophysiol. actions. In this Review, we discuss the emerging aspects of crosstalk in the nuclear receptor field and present various mechanistic crosstalk modes with examples that support applicability of the atypical heterodimer concept. Stabilization or disruption, in a context-dependent or cell type-dependent manner, of these more transient heterodimers is expected to fuel unprecedented translational approaches to yield novel therapeutic agents to treat major human diseases with higher precision.
- 23Evans, R. M.; Mangelsdorf, D. J. Nuclear Receptors, RXR, and the Big Bang. Cell 2014, 157, 255– 266, DOI: 10.1016/j.cell.2014.03.012[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmtVCqsLw%253D&md5=875fafc223c6585cf3494d3559357a4fNuclear Receptors, RXR, and the Big BangEvans, Ronald M.; Mangelsdorf, David J.Cell (Cambridge, MA, United States) (2014), 157 (1), 255-266CODEN: CELLB5; ISSN:0092-8674. (Cell Press)A review. Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional anal. revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the "Big Bang" of mol. endocrinol. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its assocd. ligands and transcriptional mechanism.
- 24Rastinejad, F.; Huang, P.; Chandra, V.; Khorasanizadeh, S. Understanding Nuclear Receptor Form and Function Using Structural Biology. J. Mol. Endocrinol. 2013, 51 (3), T1– T21, DOI: 10.1530/JME-13-0173[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXivFSnsbc%253D&md5=69abf902c2d99b23f37e33ceadd96016Understanding nuclear receptor form and function using structural biologyRastinejad, Fraydoon; Huang, Pengxiang; Chandra, Vikas; Khorasanizadeh, SepidehJournal of Molecular Endocrinology (2013), 51 (3), T1-T21CODEN: JMLEEI; ISSN:0952-5041. (BioScientifica Ltd.)A review. Nuclear receptors (NRs) are a major transcription factor family whose members selectively bind small-mol. lipophilic ligands and transduce those signals into specific changes in gene programs. For over two decades, structural biol. efforts were focused exclusively on the individual ligand-binding domains (LBDs) or DNA-binding domains of NRs. These analyses revealed the basis for both ligand and DNA binding and also revealed receptor conformations representing both the activated and repressed states. Addnl., crystallog. studies explained how NR LBD surfaces recognize discrete portions of transcriptional coregulators. The many structural snapshots of LBDs have also guided the development of synthetic ligands with therapeutic potential. Yet, the exclusive structural focus on isolated NR domains has made it difficult to conceptualize how all the NR polypeptide segments are coordinated phys. and functionally in the context of receptor quaternary architectures. Newly emerged crystal structures of the peroxisome proliferator-activated receptor-γ-retinoid X receptor α (PPARγ-RXRα) heterodimer and hepatocyte nuclear factor (HNF)-4α homodimer have recently revealed the higher order organizations of these receptor complexes on DNA, as well as the complexity and uniqueness of their domain-domain interfaces. These emerging structural advances promise to better explain how signals in one domain can be allosterically transmitted to distal receptor domains, also providing much better frameworks for guiding future drug discovery efforts.
- 25Negishi, M.; Kobayashi, K.; Sakuma, T.; Sueyoshi, T. Nuclear Receptor Phosphorylation in Xenobiotic Signal Transduction. J. Biol. Chem. 2020, 295 (45), 15210– 15225, DOI: 10.1074/jbc.REV120.007933[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38fkslOgsw%253D%253D&md5=c41bdaa5ededead6d6d5e2874d35ed52Nuclear receptor phosphorylation in xenobiotic signal transductionNegishi Masahiko; Kobayashi Kaoru; Sakuma Tsutomu; Sueyoshi TatsuyaThe Journal of biological chemistry (2020), 295 (45), 15210-15225 ISSN:.Nuclear pregnane X receptor (PXR, NR1I2) and constitutive active/androstane receptor (CAR, NR1I3) are nuclear receptors characterized in 1998 by their capability to respond to xenobiotics and activate cytochrome P450 (CYP) genes. An anti-epileptic drug, phenobarbital (PB), activates CAR and its target CYP2B genes, whereas PXR is activated by drugs such as rifampicin and statins for the CYP3A genes. Inevitably, both nuclear receptors have been investigated as ligand-activated nuclear receptors by identifying and characterizing xenobiotics and therapeutics that directly bind CAR and/or PXR to activate them. However, PB, which does not bind CAR directly, presented an alternative research avenue for an indirect ligand-mediated nuclear receptor activation mechanism: phosphorylation-mediated signal regulation. This review summarizes phosphorylation-based mechanisms utilized by xenobiotics to elicit cell signaling. First, the review presents how PB activates CAR (and other nuclear receptors) through a conserved phosphorylation motif located between two zinc fingers within its DNA-binding domain. PB-regulated phosphorylation at this motif enables nuclear receptors to form communication networks, integrating their functions. Next, the review discusses xenobiotic-induced PXR activation in the absence of the conserved DNA-binding domain phosphorylation motif. In this case, phosphorylation occurs at a motif located within the ligand-binding domain to transduce cell signaling that regulates hepatic energy metabolism. Finally, the review delves into the implications of xenobiotic-induced signaling through phosphorylation in disease development and progression.
- 26Rastinejad, F.; Ollendorff, V.; Polikarpov, I. Nuclear Receptor Full-Length Architectures: Confronting Myth and Illusion with High Resolution. Trends Biochem. Sci. 2015, 40 (1), 16– 24, DOI: 10.1016/j.tibs.2014.10.011[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFCnsbnM&md5=c290c02993f1dfda737ff644d309c7daNuclear receptor full-length architectures: confronting myth and illusion with high resolutionRastinejad, Fraydoon; Ollendorff, Vincent; Polikarpov, IgorTrends in Biochemical Sciences (2015), 40 (1), 16-24CODEN: TBSCDB; ISSN:0968-0004. (Elsevier Ltd.)A review. The crystal structures of 3 nuclear receptor (NR) complexes have emerged to reveal their multidomain architectures on DNA. These pictures provide unprecedented views of interfacial couplings between the DNA-binding domains (DBDs) and ligand-binding domains (LBDs). The detailed pictures contrast with previous interpretations of low-resoln. electron microscopy (EM) and small-angle X-ray scattering (SAXS) data, which had suggested a common architecture with non-interacting DBDs and LBDs. Revisiting both historical and recent interpretations of NR architecture, the authors invoke new principles underlying higher-order quaternary organization and the allosteric transmission of signals between domains. The authors also discuss how NR architectures are being probed in living cells to understand dimerization and DNA-binding events in real time.
- 27Weikum, E. R.; Liu, X.; Ortlund, E. A. The Nuclear Receptor Superfamily: A Structural Perspective. Protein Sci. 2018, 27, 1876– 1892, DOI: 10.1002/pro.3496[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvF2lt7zJ&md5=7ad0394bc664396a1945098246aa57b2The nuclear receptor superfamily: A structural perspectiveWeikum, Emily R.; Liu, Xu; Ortlund, Eric A.Protein Science (2018), 27 (11), 1876-1892CODEN: PRCIEI; ISSN:1469-896X. (Wiley-Blackwell)A review. Nuclear receptors (NRs) are a family of transcription factors that regulate numerous physiol. processes such as metab., reprodn., inflammation, as well as the circadian rhythm. NRs sense changes in lipid metabolite levels to drive differential gene expression, producing distinct physiol. effects. This is an allosteric process whereby binding a cognate ligand and specific DNA sequences drives the recruitment of diverse transcriptional co-regulators at chromatin and ultimately transactivation or transrepression of target genes. Dysregulation of NR signaling leads to various malignances, metabolic disorders, and inflammatory disease. Given their important role in physiol. and ability to respond to small lipophilic ligands, NRs have emerged as valuable therapeutic targets. Here, we summarize and discuss the recent progress on understanding the complex mechanism of action of NRs, primarily from a structural perspective. Finally, we suggest future studies to improve our understanding of NR signaling and better design drugs by integrating multiple structural and biophys. approaches.
- 28Bain, D. L.; Heneghan, A. F.; Connaghan-Jones, K. D.; Miura, M. T. Nuclear Receptor Structure: Implications for Function. Annu. Rev. Physiol. 2007, 69 (1), 201– 220, DOI: 10.1146/annurev.physiol.69.031905.160308[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXltVaks7o%253D&md5=e5a532a504e45489b84640efd7189f05Nuclear receptor structure: implications for functionBain, David L.; Heneghan, Aaron F.; Connaghan-Jones, Keith D.; Miura, Michael T.Annual Review of Physiology (2007), 69 (), 201-220CODEN: ARPHAD; ISSN:0066-4278. (Annual Reviews Inc.)A review. Small lipophilic mols. such as steroidal hormones, retinoids, and free fatty acids control many of the reproductive, developmental, and metabolic processes in eukaryotes. The mediators of these effects are nuclear receptor proteins, ligand-activated transcription factors capable of regulating the expression of complex gene networks. This review addresses the structure and structural properties of nuclear receptors, focusing on the well-studied ligand-binding and DNA-binding domains as well as the still-emerging understanding of the largely unstructured N-terminal regions. To emphasize the allosteric interdependence among these subunits, a more detailed inspection of the structural properties of the human progesterone receptor is presented. Finally, this work is placed in the context of developing a quant. and mechanistic understanding of nuclear receptor function.
- 29Benoit, G.; Cooney, A.; Giguere, V.; Ingraham, H.; Lazar, M.; Muscat, G.; Perlmann, T.; Renaud, J.-P.; Schwabe, J.; Sladek, F.; Tsai, M.-J.; Laudet, V. International Union of Pharmacology. LXVI. Orphan Nuclear Receptors. Pharmacol. Rev. 2006, 58 (4), 798– 836, DOI: 10.1124/pr.58.4.10[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1aitg%253D%253D&md5=dd46a5a87b58b13f720cd63d864b7c86International union of pharmacology. LXVI. Orphan nuclear receptorsBenoit, Gerard; Cooney, Austin; Giguere, Vincent; Ingraham, Holly; Lazar, Mitch; Muscat, George; Perlmann, Thomas; Renaud, Jean-Paul; Schwabe, John; Sladek, Frances; Tsai, Ming-Jer; Laudet, VincentPharmacological Reviews (2006), 58 (4), 798-836CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. Half of the members of the nuclear receptors superfamily are so-called "orphan" receptors because the identity of their ligand, if any, is unknown. Because of their important biol. roles, the study of orphan receptors has attracted much attention recently and has resulted in rapid advances that have helped in the discovery of novel signaling pathways. In this review we present the main features of orphan receptors, discuss the structure of their ligand-binding domains and their biol. functions. The paradoxical existence of a pharmacol. of orphan receptors, a rapidly growing and innovative field, is highlighted.
- 30Robinson-Rechavi, M.; Garcia, H. E.; Laudet, V. The Nuclear Receptor Superfamily. J. Cell Sci. 2003, 116 (4), 585– 586, DOI: 10.1242/jcs.00247[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252FjtFamuw%253D%253D&md5=ac244dd3bf3de2a5ff92fd43fe8f5959The nuclear receptor superfamilyRobinson-Rechavi Marc; Escriva Garcia Hector; Laudet VincentJournal of cell science (2003), 116 (Pt 4), 585-6 ISSN:0021-9533.There is no expanded citation for this reference.
- 31Michalik, L.; Auwerx, J.; Berger, J. P.; Chatterjee, V. K.; Glass, C. K.; Gonzalez, F. J.; Grimaldi, P. A.; Kadowaki, T.; Lazar, M. A.; O’Rahilly, S.; Palmer, C. N. A.; Plutzky, J.; Reddy, J. K.; Spiegelman, B. M.; Staels, B.; Wahli, W. International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors. Pharmacol. Rev. 2006, 58 (4), 726– 741, DOI: 10.1124/pr.58.4.5[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1ajuw%253D%253D&md5=938a3c0f6da60bde927e3b1822f7d12bInternational union of pharmacology. LXI. Peroxisome proliferator-activated receptorsMichalik, Liliane; Auwerx, Johan; Berger, Joel P.; Chatterjee, V. Krishna; Glass, Christopher K.; Gonzalez, Frank J.; Grimaldi, Paul A.; Kadowaki, Takashi; Lazar, Mitchell A.; O'Rahilly, Stephen; Palmer, Colin N. A.; Plutzky, Jorge; Reddy, Janardan K.; Spiegelman, Bruce M.; Staels, Bart; Wahli, WalterPharmacological Reviews (2006), 58 (4), 726-741CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. The three peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. They share a high degree of structural homol. with all members of the superfamily, particularly in the DNA-binding domain and ligand- and cofactor-binding domain. Many cellular and systemic roles have been attributed to these receptors, reaching far beyond the stimulation of peroxisome proliferation in rodents after which they were initially named. PPARs exhibit broad, isotype-specific tissue expression patterns. PPARα is expressed at high levels in organs with significant catabolism of fatty acids. PPARβ/δ has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPARγ is expressed as two isoforms, of which PPARγ2 is found at high levels in the adipose tissues, whereas PPARγ1 has a broader expression pattern. Transcriptional regulation by PPARs requires heterodimerization with the retinoid X receptor (RXR). When activated by a ligand, the dimer modulates transcription via binding to a specific DNA sequence element called a peroxisome proliferator response element (PPRE) in the promoter region of target genes. A wide variety of natural or synthetic compds. was identified as PPAR ligands. Among the synthetic ligands, the lipid-lowering drugs, fibrates, and the insulin sensitizers, thiazolidinediones, are PPARα and PPARγ agonists, resp., which underscores the important role of PPARs as therapeutic targets. Transcriptional control by PPAR/RXR heterodimers also requires interaction with coregulator complexes. Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities.
- 32Warden, A.; Truitt, J.; Merriman, M.; Ponomareva, O.; Jameson, K.; Ferguson, L. B.; Mayfield, R. D.; Harris, R. A. Localization of PPAR Isotypes in the Adult Mouse and Human Brain. Sci. Rep. 2016, 6, 27681, DOI: 10.1038/srep27618
- 33Gellrich, L.; Heitel, P.; Heering, J.; Kilu, W.; Pollinger, J.; Goebel, T.; Kahnt, A.; Arifi, S.; Pogoda, W.; Paulke, A.; Steinhilber, D.; Proschak, E.; Wurglics, M.; Schubert-Zsilavecz, M.; Chaikuad, A.; Knapp, S.; Bischoff, I.; Fürst, R.; Merk, D. L-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ. J. Med. Chem. 2020, 63 (13), 6727– 6740, DOI: 10.1021/acs.jmedchem.9b02150[ACS Full Text
], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXotl2qt7k%253D&md5=ef11092bf1432477ab92bda15bf37c46L-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγGellrich, Leonie; Heitel, Pascal; Heering, Jan; Kilu, Whitney; Pollinger, Julius; Goebel, Tamara; Kahnt, Astrid; Arifi, Silvia; Pogoda, Werner; Paulke, Alexander; Steinhilber, Dieter; Proschak, Ewgenij; Wurglics, Mario; Schubert-Zsilavecz, Manfred; Chaikuad, Apirat; Knapp, Stefan; Bischoff, Iris; Fuerst, Robert; Merk, DanielJournal of Medicinal Chemistry (2020), 63 (13), 6727-6740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Thyroid hormones (THs) operate numerous physiol. processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and non-classical THs as another mol. activity of THs. The T4 metabolite TETRAC was the most active TH on PPARγ with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular and in vivo settings. Simultaneous activation of the heterodimer partners PPARγ and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARγ and RXR, TETRAC differs markedly in its mol. structure and the PPARγ-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacol. - 34Proschak, E.; Heitel, P.; Kalinowsky, L.; Merk, D. Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery. J. Med. Chem. 2017, 60 (13), 5235– 5266, DOI: 10.1021/acs.jmedchem.6b01287[ACS Full Text], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjs1elsrw%253D&md5=78a3a6be0a9d9bfd672c5e851abffc3eOpportunities and Challenges for Fatty Acid Mimetics in Drug DiscoveryProschak, Ewgenij; Heitel, Pascal; Kalinowsky, Lena; Merk, DanielJournal of Medicinal Chemistry (2017), 60 (13), 5235-5266CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Fatty acids beyond their role as an endogenous energy source and storage are increasingly considered as signaling mols. regulating various physiol. effects in metab. and inflammation. Accordingly, the mol. targets involved in formation and physiol. activities of fatty acids hold significant therapeutic potential. A no. of these fatty acid targets are addressed by some of the oldest and most widely used drugs such as cyclooxygenase inhibiting NSAIDs, whereas others remain unexploited. Compds. orthosterically binding to proteins that endogenously bind fatty acids are considered as fatty acid mimetics. On the basis of their structural resemblance, fatty acid mimetics constitute a family of bioactive compds. showing specific binding thermodn. and following similar pharmacokinetic mechanisms. This perspective systematically evaluates targets for fatty acid mimetics, investigates their common structural characteristics, and highlights demands in their discovery and design. In summary, fatty acid mimetics share particularly favorable characteristics justifying the conclusion that their therapeutic potential vastly outweighs the challenges in their design.
- 35Wahli, W.; Michalik, L. PPARs at the Crossroads of Lipid Signaling and Inflammation. Trends Endocrinol. Metab. 2012, 23, 351– 363, DOI: 10.1016/j.tem.2012.05.001[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XosFChur4%253D&md5=c75c774b268207244eb1ba0e476633efPPARs at the crossroads of lipid signaling and inflammationWahli, Walter; Michalik, LilianeTrends in Endocrinology and Metabolism (2012), 23 (7), 351-363CODEN: TENME4; ISSN:1043-2760. (Elsevier Ltd.)A review. Nuclear receptors (NRs) are ligand-dependent transcription factors whose activation affects genes controlling vital processes. Among them, the peroxisome proliferator-activated receptors (PPARs) have emerged as links between lipids, metabolic diseases, and innate immunity. PPARs are activated by fatty acids and their derivs., many of which also signal through membrane receptors, thereby creating a lipid signaling network between the cell surface and the nucleus. Tissues that play a role in whole-body metabolic homeostasis, such as adipose tissue, liver, skeletal muscle, intestines, and blood vessel walls, are prone to inflammation when metab. is disturbed, a complication that promotes type 2 diabetes and cardiovascular disease. This review discusses the protective roles of PPARs in inflammatory conditions and the therapeutic anti-inflammatory potential of PPAR ligands.
- 36Lamers, C.; Schubert-Zsilavecz, M.; Merk, D. Therapeutic Modulators of Peroxisome Proliferator-Activated Receptors (PPAR): A Patent Review (2008–Present). Expert Opin. Ther. Pat. 2012, 22 (7), 803– 841, DOI: 10.1517/13543776.2012.699042[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XptVGrtbw%253D&md5=302d4f63a185c451514dd032becc3c3bTherapeutic modulators of peroxisome proliferator-activated receptors (PPAR): a patent review (2008-present)Lamers, Christina; Schubert-Zsilavecz, Manfred; Merk, DanielExpert Opinion on Therapeutic Patents (2012), 22 (7), 803-841CODEN: EOTPEG; ISSN:1354-3776. (Informa Healthcare)A review. Introduction: Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. The three known subtypes PPARα, PPARγ and PPARδ have different tissue distribution and play a key role as regulators of glucose and lipid homeostasis as well as in cell proliferation, differentiation and inflammatory responses. They have gained a lot of interest as pharmaceutical targets over the last years and with the antidiabetic thiazolidindiones (TZDs) and the hypolipidemic fibrates, two classes of drugs had entered the market. Early observations of severe adverse events changed the situation in the recent past. Areas covered: Herein the authors summarize recent (2008-present) patent applications concerning PPAR ligands claimed for the use in metabolic disorders as well as patents indicating new applications for modulators of the PPAR subtypes.Expert opinion: Looking at the recent patent activity regarding novel compds., there have not been real innovations. As major applications for therapeutic PPAR ligands cancer therapy, skin-related disorders and systemic anti-inflammatory therapies might arise in the mid-term future. The known PPAR targeting drugs might see a repurposing for novel indications.
- 37Lu, C.-H.; Yang, C.-Y.; Li, C.-Y.; Hsieh, C.; Ou, H.-T. Lower Risk of Dementia with Pioglitazone, Compared with Other Second-Line Treatments, in Metformin-Based Dual Therapy: A Population-Based Longitudinal Study. Diabetologia 2018, 61 (3), 562– 573, DOI: 10.1007/s00125-017-4499-5[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVSmsLjP&md5=9b392b0512f3e11c9f7a627fe6b751bbLower risk of dementia with pioglitazone, compared with other second-line treatments, in metformin-based dual therapy: a population-based longitudinal studyLu, Chieh-Hsiang; Yang, Chen-Yi; Li, Chung-Yi; Hsieh, Cheng-Yang; Ou, Huang-TzDiabetologia (2018), 61 (3), 562-573CODEN: DBTGAJ; ISSN:0012-186X. (Springer)Aims/hypothesis: The effect of pioglitazone was compared with that of other second-line glucose-lowering drugs on the risk of dementia among individuals with type 2 diabetes receiving metformin-based dual therapy. Methods: A total of 204,323 individuals with type 2 diabetes aged ≥18 years who were stable metformin users and dementia-free before the initiation of second-line glucose-lowering medication were identified in the period 2000-2011 from Taiwan's National Health Insurance Research Database and followed to the end of 2013. Primary analyses included 51,415 individuals aged ≥65 years without dementia events in the first year of second-line glucose-lowering treatment. Study subjects were classified into mutually exclusive groups according to various second-line glucose-lowering drugs to metformin. Cox proportional hazards models were applied to assess the time-to-event between propensity score-matched glucose-lowering treatment groups. Results: Individuals aged ≥65 years on metformin + pioglitazone had a significantly lower risk of dementia compared with those on metformin + sulfonylurea (HR 0.56; 95% CI 0.34, 0.93), and a lower, but insignificant, risk of dementia compared with those on other metformin-based dual regimens (i.e. metformin + acarbose, metformin + meglitinide, metformin + insulin or metformin + dipeptidyl peptidase 4 inhibitors). Among individuals aged ≥18 years, there was also a decreased risk of dementia in those taking pioglitazone compared with those taking other second-line glucose-lowering drugs. A lower incidence of dementia was found in users of metformin + pioglitazone compared with users of metformin + rosiglitazone. Conclusions/interpretation: Pioglitazone as a second-line treatment after metformin might provide a protective effect on dementia risk among individuals with type 2 diabetes.
- 38Heneka, M. T.; Fink, A.; Doblhammer, G. Effect of Pioglitazone Medication on the Incidence of Dementia. Ann. Neurol. 2015, 78 (2), 284– 294, DOI: 10.1002/ana.24439[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KmsLbJ&md5=9eecf871dfb506e716f9518f86542655Effect of pioglitazone medication on the incidence of dementiaHeneka, Michael T.; Fink, Anne; Doblhammer, GabrieleAnnals of Neurology (2015), 78 (2), 284-294CODEN: ANNED3; ISSN:0364-5134. (John Wiley & Sons, Inc.)Objective : Peroxisome proliferator activated receptor γ-activating drugs show various salutary effects in preclin. models of neurodegenerative disease. The decade-long clin. usage of these drugs as antidiabetics now allows for evaluation of patient-oriented data sources. Methods : Using observational data from 2004-2010, we analyzed the assocn. of pioglitazone and incidence of dementia in a prospective cohort study of 145,928 subjects aged ≥60 years who, at baseline, were free of dementia and insulin-dependent diabetes mellitus. We distinguished between nondiabetics, diabetics without pioglitazone, diabetics with prescriptions of <8 calendar quarters of pioglitazone, and diabetics with ≥8 quarters. Cox proportional hazard models explored the relative risk (RR) of dementia incidence dependent on pioglitazone use adjusted for sex, age, use of rosiglitazone or metformin, and cardiovascular comorbidities. Results : Long-term use of pioglitazone was assocd. with a lower dementia incidence. Relative to nondiabetics, the cumulative long-term use of pioglitazone reduced the dementia risk by 47% (RR = 0.53, p = 0.029). If diabetes patients used pioglitazone <8 quarters, the dementia risk was comparable to those of nondiabetics (RR = 1.16, p = 0.317), and diabetes patients without a pioglitazone treatment had a 23% increase in dementia risk (RR = 1.23, p < 0.001). We did not find evidence for age effects, nor for selection into pioglitazone treatment due to obesity. Interpretation : These findings indicate that pioglitazone treatment is assocd. with a reduced dementia risk in initially non-insulin-dependent diabetes mellitus patients. Prospective clin. trials are needed to evaluate a possible neuroprotective effect in these patients in an ageing population. Ann Neurol 2015;78:284-294.
- 39Chou, P.-S.; Ho, B.-L.; Yang, Y.-H. Effects of Pioglitazone on the Incidence of Dementia in Patients with Diabetes. J. Diabetes Complications 2017, 31 (6), 1053– 1057, DOI: 10.1016/j.jdiacomp.2017.01.006[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czitlSitA%253D%253D&md5=d35451551f14800a3f1ba2a1d796ad33Effects of pioglitazone on the incidence of dementia in patients with diabetesChou Ping-Song; Ho Bo-Lin; Yang Yuan-HanJournal of diabetes and its complications (2017), 31 (6), 1053-1057 ISSN:.AIMS: Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists exert neuroprotective effects in the brain. Therefore, in this population-based cohort study, we investigated the effects of pioglitazone, a PPAR-γ agonist, on the risk of dementia. METHODS: By using claims data from Taiwan's National Health Insurance Research Database, we included 6401 patients with diabetes who were treated with pioglitazone and 12,802 age- and sex-matched patients with diabetes who were never treated with pioglitazone from 2004 to 2009 and who were free of dementia at baseline. RESULTS: In total, 113 (1.8%) and 323 (2.5%) patients in the pioglitazone-treated and comparison cohorts, respectively, developed dementia during the 5-year follow-up. The risk of dementia decreased by 23% in the pioglitazone-treated cohort compared with that in the comparison cohort after adjustment for age, sex, hypertension, and stroke (adjusted hazard ratio [HR], 0.77; 95% confidence interval [CI]=0.62-0.96). In addition, the adjusted HRs (95% CIs) for dementia were 0.50 (0.34-0.75, P=.001) in high-cumulative dose users, 0.53 (0.36-0.77, P<.001) in long-term users, and 0.66 (0.49-0.90, P=.009) in high-mean daily dose users. CONCLUSIONS: Pioglitazone is a time- and dose-dependent protective factor against dementia in patients with diabetes. The risk of dementia is lower in long-term and high-dose pioglitazone users than in never users of pioglitazone.
- 40Kummer, M. P.; Heneka, M. T. PPARs in Alzheimer’s Disease. PPAR Res. 2008, 2008, 403896, DOI: 10.1155/2008/403896[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cvmslWqtA%253D%253D&md5=6a54ae24b134f720094fab1c67e49e9cPPARs in Alzheimer's DiseaseKummer Markus P; Heneka Michael TPPAR research (2008), 2008 (), 403896 ISSN:1687-4757.Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the neurodegeneration and the deposition of the beta-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARgamma. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARgamma. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPARgamma receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD.
- 41Heneka, M. T.; Reyes-Irisarri, E.; Hull, M.; Kummer, M. P. Impact and Therapeutic Potential of PPARs in Alzheimers Disease. Curr. Neuropharmacol. 2011, 9 (4), 643– 650, DOI: 10.2174/157015911798376325[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFWhs74%253D&md5=4c6faf8a714bc696eb130266005b5b09Impact and therapeutic potential of PPARs in Alzheimer's diseaseHeneka, Michael T.; Reyes-Irisarri, Elisabet; Huell, Michael; Kummer, Markus P.Current Neuropharmacology (2011), 9 (4), 643-650CODEN: CNUEAN; ISSN:1875-6190. (Bentham Science Publishers Ltd.)A review. Peroxisome proliferator activated receptors (PPARs) are well studied for their role of peripheral metab., but they also may be involved in the pathogenesis of various disorders of the central nervous system (CNS) including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's and, Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases, lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the deposition of the β-amyloid peptide in extracellular plaques and ongoing neurodegeneration. Non-steroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD related transgenic cellular and animal models. Stimulation of PPARγ by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic and insulin sensitizing effects may account for the obsd. effects. Several clin. trials already revealed promising results using PPARγ agonists, therefore PPARγ represents an attractive therapeutic target for the treatment of AD.
- 42Du, J.; Zhang, L.; Liu, S.; Zhang, C.; Huang, X.; Li, J.; Zhao, N.; Wang, Z. PPARγ Transcriptionally Regulates the Expression of Insulin-Degrading Enzyme in Primary Neurons. Biochem. Biophys. Res. Commun. 2009, 383 (4), 485– 490, DOI: 10.1016/j.bbrc.2009.04.047[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXls1KhsLk%253D&md5=5aa4a9fd88960a81de738c22a74c61efPPARγ transcriptionally regulates the expression of insulin-degrading enzyme in primary neuronsDu, Jing; Zhang, Lang; Liu, Shubo; Zhang, Chi; Huang, Xiuqing; Li, Jian; Zhao, Nanming; Wang, ZhaoBiochemical and Biophysical Research Communications (2009), 383 (4), 485-490CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Insulin-degrading enzyme (IDE) is a protease that has been demonstrated to play a key role in degrading both Aβ and insulin and deficient in IDE function is assocd. with Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2) pathol. However, little is known about the cellular and mol. regulation of IDE expression. Here we show IDE levels are markedly decreased in DM2 patients and pos. correlated with the peroxisome proliferator-activated receptor γ (PPARγ) levels. Further studies show that PPARγ plays an important role in regulating IDE expression in rat primary neurons through binding to a functional peroxisome proliferator-response element (PPRE) in IDE promoter and promoting IDE gene transcription. Finally, we demonstrate that PPARγ participates in the insulin-induced IDE expression in neurons. These results suggest that PPARγ transcriptionally induces IDE expression which provides a novel mechanism for the use of PPARγ agonists in both DM2 and AD therapies.
- 43Quan, Q.; Qian, Y.; Li, X.; Li, M. Pioglitazone Reduces β Amyloid Levels via Inhibition of PPARγ Phosphorylation in a Neuronal Model of Alzheimer’s Disease. Front. Aging Neurosci. 2019, 11, 178, DOI: 10.3389/fnagi.2019.00178[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjs1yjur8%253D&md5=f459cb455831b4a9f07ae435f5dfdbb3Pioglitazone reduces β amyloid levels via inhibition of PPARγ phosphorylation in a neuronal model of Alzheimer's diseaseQuan, Qiankun; Qian, Yihua; Li, Xi; Li, MingFrontiers in Aging Neuroscience (2019), 11 (), 178CODEN: FANRC5; ISSN:1663-4365. (Frontiers Media S.A.)It has been demonstrated that peroxisome proliferator-activated receptor γ (PPARγ) can regulate the transcription of its target gene, insulin-degrading enzyme (IDE), and thus enhance the expression of the IDE protein. The protein can degrade β amyloid (Aβ), a core pathol. product of Alzheimer's disease (AD). PPARγ can also regulate the transcription of other target gene, β-amyloid cleavage enzyme 1 (BACE1), and thus inhibit the expression of the BACE1 protein. BACE1 can hydrolyze amyloid precursor protein (APP), the precursor of Aβ. In adipose tissue, PPARγ agonists can inhibit the phosphorylation of PPARγ by inhibiting cyclin-dependent kinase 5 (CDK5), which in turn affects the expression of target genes regulated by PPARγ. PPARγ agonists may also exert inhibitory effects on the phosphorylation of PPARγ in the brain, thereby affecting the expression of the aforementioned PPARγ target genes and reducing Aβ levels. The present study confirmed this hypothesis by showing that PPARγ agonist pioglitazone attenuated the neuronal apoptosis of primary rat hippocampal neurons induced by Aβ1-42, downregulated CDK5 expression, weakened the binding of CDK5 to PPARγ, reduced PPARγ phosphorylation, increased the expression of PPARγ and IDE, decreased the expression of BACE1, reduced APP prodn., and downregulated intraneuronal Aβ1-42 levels. These effects were inhibited by the PPARγ antagonist GW9662. After CDK5 silencing with CDK5 shRNA, the above effect of pioglitazone was not obsd., except when upregulating the expression of PPARγ in Aβ1-42 treated neurons. In conclusion, this study demonstrated that pioglitazone could inhibit the phosphorylation of PPARγ in vitro by inhibiting CDK5 expression, which in turn affected the expression of PPARγ target genes Ide and Bace1, thereby promoting Aβ degrdn. and reducing Aβ prodn. This reduced Aβ levels in the brain, thereby exerting neuroprotective effects in an AD model.
- 44Sastre, M.; Dewachter, I.; Rossner, S.; Bogdanovic, N.; Rosen, E.; Borghgraef, P.; Evert, B. O.; Dumitrescu-Ozimek, L.; Thal, D. R.; Landreth, G.; Walter, J.; Klockgether, T.; Van Leuven, F.; Heneka, M. T. Nonsteroidal Anti-Inflammatory Drugs Repress β-Secretase Gene Promoter Activity by the Activation of PPARγ. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (2), 443– 448, DOI: 10.1073/pnas.0503839103[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XpsVSluw%253D%253D&md5=ff887abb8a138a2539a859295887c0a3Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγSastre, Magdalena; Dewachter, Ilse; Rossner, Steffen; Bogdanovic, Nenad; Rosen, Evan; Borghgraef, Peter; Evert, Bernd O.; Dumitrescu-Ozimek, Lucia; Thal, Dietmar R.; Landreth, Gary; Walter, Jochen; Klockgether, Thomas; van Leuven, Fred; Heneka, Michael T.Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (2), 443-448CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Epidemiol. evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated receptor-γ (PPARγ), which is a nuclear transcriptional regulator. Here we show that PPARγ depletion potentiates β-secretase [β-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARγ, as well as NSAIDs and PPARγ activators, reduced BACE1 gene promoter activity. These results suggested that PPARγ could be a repressor of BACE1. We then identified a PPARγ responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARγ to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPARγ gene transcription, and this effect was suppressed by NSAIDs. We also demonstrate that in vivo treatment with PPARγ agonists increased PPARγ and reduced BACE1 mRNA and intracellular β-amyloid levels. Interestingly, brain exts. from AD patients showed decreased PPARγ expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPARγ in the modulation of amyloid-β generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPARγ and decreased BACE1 gene transcription.
- 45Sastre, M.; Dewachter, I.; Landreth, G. E.; Willson, T. M.; Klockgether, T.; Van Leuven, F.; Heneka, M. T. Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor-γ Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of β-Secretase. J. Neurosci. 2003, 23 (30), 9796– 9804, DOI: 10.1523/JNEUROSCI.23-30-09796.2003[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXovVKis7w%253D&md5=b7e010a3cc3774b7f42444da3a49324aNonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-γ agonists modulate immunostimulated processing of amyloid precursor protein through regulation of β-secretaseSastre, Magdalena; Dewachter, Ilse; Landreth, Gary E.; Willson, Timothy M.; Klockgether, Thomas; van Leuven, Fred; Heneka, Michael T.Journal of Neuroscience (2003), 23 (30), 9796-9804CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk for Alzheimer's disease (AD). To det. the mechanisms by which inflammation affects AD and how NSAIDs protect against it, we stimulated neuroblastoma cells stably transfected with amyloid precursor protein (APP) with proinflammatory cytokines, which increased the secretion of amyloid-β and APP ectodomain. Addn. of ibuprofen, indomethacin, peroxisome proliferator-activated receptor-γ (PPARγ) agonists, or cotransfection with PPARγ cDNA reversed this effect. The inhibitory action of ibuprofen and indomethacin was suppressed by PPARγ antagonists. Finally, we obsd. that the mRNA levels, expression, and enzymic activity of β-secretase were increased by immunostimulation and normalized by NSAIDs. In conclusion, proinflammatory cytokines activate β-secretase, and NSAIDs inhibit this effect through PPARγ.
- 46Yang, S.; Chen, Z.; Cao, M.; Li, R.; Wang, Z.; Zhang, M. Pioglitazone Ameliorates Aβ42 Deposition in Rats with Diet-Induced Insulin Resistance Associated with AKT/GSK3β Activation. Mol. Med. Rep. 2017, 15 (5), 2588– 2594, DOI: 10.3892/mmr.2017.6342[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFWktrbN&md5=709e610125cc5179b3b340951ea31696Pioglitazone ameliorates Aβ42 deposition in rats with diet-induced insulin resistance associated with AKT/GSK3β activationYang, Sisi; Chen, Zhe; Cao, Ming; Li, Renjie; Wang, Zhigang; Zhang, MuxunMolecular Medicine Reports (2017), 15 (5), 2588-2594CODEN: MMROA5; ISSN:1791-3004. (Spandidos Publications Ltd.)Pioglitazone may have potential benefits as an alternative therapeutic treatment for patients with Alzheimer's disease (AD), particularly in individuals that also have comorbid diabetes; however, the mechanisms of action remain unclear. The present study aimed to explore the effects of pioglitazone on amyloid β, isoform 42 (Aβ42) deposition in rats with diet-induced insulin resistance (IR). Diet-induced IR model rats were established in the presence or absence of pioglitazone. Plasma glucose and insulin levels, and cerebrospinal fluid insulin levels were measured; in addn., hippocampal tissues were collected for immunohistochem. anal. of Aβ42 expression. The levels of insulin-degrading enzyme (IDE) and peroxisome proliferator-activated receptor γ (PPARγ) mRNA and protein expression were analyzed by reverse transcription-quant. polymerase chain reaction and western blotting, resp. In addn., the activation of glycogen synthase kinase 3β (GSK3β) induced by phosphatidylinositol 3-kinase (PI3K) /protein kinase B (AKT) signaling was detected by western blotting. Results from the present study demonstrated that pioglitazone may enhance peripheral and brain insulin sensitivity in diet-induced IR model rats. Treatment with pioglitazone ameliorated Aβ42 deposition in the hippocampus by increasing IDE and PPARγ expression. Notably, activation of the PI3K/AKT/GSK3β pathway was also demonstrated to serve a role in pioglitazone-induced Aβ42 degrdn., which was abrogated by the PPARγ antagonist GW9662. Results from the present study indicated that pioglitazone may improve insulin sensitivity and ameliorate Aβ42 accumulation in rats with diet-induced IR by regulating AKT/GSK3β activation, suggesting that pioglitazone may be a promising drug for AD treatment.
- 47Chang, K. L.; Wong, L. R.; Pee, H. N.; Yang, S.; Ho, P. C. L. Reverting Metabolic Dysfunction in Cortex and Cerebellum of APP/PS1Mice, a Model for Alzheimer’s Disease by Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist. Mol. Neurobiol. 2019, 56 (11), 7267– 7283, DOI: 10.1007/s12035-019-1586-2[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXosF2qu74%253D&md5=22df1faf51285ab5c7074da6312d564fReverting Metabolic Dysfunction in Cortex and Cerebellum of APP/PS1 Mice, a Model for Alzheimer's Disease by Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma) AgonistChang, Kai Lun; Wong, Ling Rong; Pee, Hai Ning; Yang, Shili; Ho, Paul Chi-LuiMolecular Neurobiology (2019), 56 (11), 7267-7283CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Identification of mol. mechanisms underlying early-stage Alzheimer's disease (AD) is important for the development of new therapies against and diagnosis of AD. In this study, gas chromatog. time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics approach was employed to investigate the metabolic profiles in plasma and brain tissues harvested from 5-mo-old APP/PS1 transgenic mice and their wildtype counterparts. Since different brain regions were expected to have their own distinct metabolic signals, four different brain regions, namely cortex, hippocampus, midbrain and cerebellum tissues, were dissected and had their metabolic profiles studied sep. Biochem. assays were also performed on plasma and brain cortex tissue of transgenic mice and wildtype mice, with a focus on mitochondrial health. Our findings include the observation of extensive metabolic alterations in cortex and cerebellum of APP/PS1 mice, but not in their hippocampus, midbrain and plasma. The major pathways affected in cortex and cerebellum of APP/PS1 mice were closely related to impaired energy metab. and perturbation of amino acid metab. in these mice. Treatment with the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist pioglitazone (PIO) successfully restored the energy metab., lowered amyloid-beta levels and afforded the APP/PS1 mice a better antioxidative capacity in their cortex.
- 48Yu, Y.; Li, X.; Blanchard, J.; Li, Y.; Iqbal, K.; Liu, F.; Gong, C.-X. Insulin Sensitizers Improve Learning and Attenuate Tau Hyperphosphorylation and Neuroinflammation in 3xTg-AD Mice. J. Neural Transm. 2015, 122 (4), 593– 606, DOI: 10.1007/s00702-014-1294-z[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlamsbbI&md5=5ecc0beb6f4f83df2022e50a82a280d1Insulin sensitizers improve learning and attenuate tau hyperphosphorylation and neuroinflammation in 3xTg-AD miceYu, Yang; Li, Xiaojing; Blanchard, Julie; Li, Yi; Iqbal, Khalid; Liu, Fei; Gong, Cheng-XinJournal of Neural Transmission (2015), 122 (4), 593-606CODEN: JNTRF3; ISSN:0300-9564. (Springer-Verlag GmbH)A review. Sporadic Alzheimer's disease (AD) is a multifactorial metabolic brain disorder characterized by progressive neurodegeneration. Decreased brain energy and glucose metab. occurs before the appearance of AD symptoms and worsens while the disease progresses. Deregulated brain insulin signaling has also been found in AD recently. To restore brain insulin sensitivity and glucose metab., pioglitazone and rosiglitazone, two insulin sensitizers commonly used for treating type 2 diabetes, have been studied and shown to have some beneficial effects in AD mouse models. However, the mol. mechanisms of the beneficial effects remain elusive. In the present study, we treated the 3xTg-AD mice, a widely used mouse model of AD, with pioglitazone and rosiglitazone for 4 mo and studied the effects of the treatments on cognitive performance and AD-related brain alterations. We found that the chronic treatment improved spatial learning, enhanced AKT signaling, and attenuated tau hyperphosphorylation and neuroinflammation. These findings shed new light on the possible mechanisms by which these two insulin sensitizers might be useful for treating AD and support further clin. trials evaluating the efficacy of these drugs.
- 49Du, J.; Sun, B.; Chen, K.; Fan, L.; Wang, Z. Antagonist of Peroxisome Proliferator-Activated Receptor γ Induces Cerebellar Amyloid-β Levels and Motor Dysfunction in APP/PS1 Transgenic Mice. Biochem. Biophys. Res. Commun. 2009, 384 (3), 357– 361, DOI: 10.1016/j.bbrc.2009.04.148[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmsVCqsro%253D&md5=a1354eb3b803c5aba1cb82a3764569f0Antagonist of peroxisome proliferator-activated receptor γ induces cerebellar amyloid-β levels and motor dysfunction in APP/PS1 transgenic miceDu, Jing; Sun, Bing; Chen, Kui; Fan, Li; Wang, ZhaoBiochemical and Biophysical Research Communications (2009), 384 (3), 357-361CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Recent evidences show that peroxisome proliferator-activated receptor γ (PPARγ) is involved in the modulation of the amyloid-β (Aβ) cascade causing Alzheimer's disease (AD) and treatment with PPARγ agonists protects against AD pathol. However, the function of PPARγ steady-state activity in Aβ cascade and AD pathol. remains unclear. In this study, an antagonist of PPARγ, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPARγ activity in cerebellum. The results show that inhibition of PPARγ significantly induced Aβ levels in cerebellum and caused cerebellar motor dysfunction in APP/PS1 transgenic mice. Moreover, GW9662 treatment markedly decreased the cerebellar levels of insulin-degrading enzyme (IDE), which is responsible for the cellular degrdn. of Aβ. Since cerebellum is spared from significant Aβ accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPARγ steady-state activity in protection of cerebellum against AD pathol.
- 50Fernandez-Martos, C. M.; Atkinson, R. A. K.; Chuah, M. I.; King, A. E.; Vickers, J. C. Combination Treatment with Leptin and Pioglitazone in a Mouse Model of Alzheimer’s Disease. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2017, 3 (1), 92– 106, DOI: 10.1016/j.trci.2016.11.002
- 51Chen, J.; Li, S.; Sun, W.; Li, J. Anti-Diabetes Drug Pioglitazone Ameliorates Synaptic Defects in AD Transgenic Mice by Inhibiting Cyclin-Dependent Kinase5 Activity. PLoS One 2015, 10, e0123864 DOI: 10.1371/journal.pone.0123864[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslCrs7zO&md5=a359296d8fc981800214658afd5064e3Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activityChen, Jinan; Li, Shenghua; Sun, Wenshan; Li, JunrongPLoS One (2015), 10 (4), e0123864/1-e0123864/12CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is activated by the neuron specific activators p35/p39 and plays many important roles in neuronal development. However, aberrant activation of Cdk5 is believed to be assocd. with the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Here in the present study, enhanced Cdk5 activity was obsd. in mouse models of AD; whereas sol. amyloid-β oligomers (Aβ), which contribute to synaptic failures during AD pathogenesis, induced Cdk5 hyperactivation in cultured hippocampal neurons. Inhibition of Cdk5 activity by pharmacol. or genetic approaches reversed dendritic spine loss caused by sol. amyloid-β oligomers (Aβ) treatment. Interestingly, we found that the anti-diabetes drug pioglitazone could inhibit Cdk5 activity by decreasing p35 protein level. More importantly, pioglitazone treatment cor. long-term potentiation (LTP) deficit caused by Aβ exposure in cultured slices and pioglitazone administration rescued impaired LTP and spatial memory in AD mouse models. Taken together, our study describes an unanticipated role of pioglitazone in alleviating AD and reveals a potential therapeutic drug for AD curing.
- 52Mandrekar-Colucci, S.; Karlo, J. C.; Landreth, G. E. Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer’s Disease. J. Neurosci. 2012, 32 (30), 10117– 10128, DOI: 10.1523/JNEUROSCI.5268-11.2012[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFart7%252FL&md5=20dfa3dc6ded1b482798a7f33ed60dd6Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's diseaseMandrekar-Colucci, Shweta; Karlo, J. Colleen; Landreth, Gary E.Journal of Neuroscience (2012), 32 (30), 10117-10128CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Alzheimer's disease is assocd. with a disruption of amyloid β (Aβ) homeostasis, resulting in the accumulation and subsequent deposition of Aβ peptides within the brain. The peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor that acts in a coupled metabolic cycle with Liver X Receptors (LXRs) to increase brain apolipoprotein E (apoE) levels. ApoE functions to promote the proteolytic clearance of sol. forms of Aβ, and we found that the synthetic PPARγ agonist, pioglitazone, stimulated Aβ degrdn. by both microglia and astrocytes in an LXR and apoE-dependent manner. Remarkably, a brief 9 d oral treatment of APPswe/PS1Δe9 mice with pioglitazone resulted in dramatic redns. in brain levels of sol. and insol. Aβ levels which correlated with the loss of both diffuse and dense-core plaques within the cortex. The removal of preexisting amyloid deposits was assocd. with the appearance of abundant Aβ-laden microglia and astrocytes. Pioglitazone treatment resulted in the phenotypic polarization of microglial cells from a proinflammatory M1 state, into an anti-inflammatory M2 state that was assocd. with enhanced phagocytosis of deposited forms of amyloid. The redn. in amyloid levels was assocd. with a reversal of contextual memory deficits in the drug-treated mice. These data provide a mechanistic explanation for how PPARγ activation facilitates amyloid clearance and supports the therapeutic utility of PPARγ agonists for the treatment of Alzheimer's disease.
- 53Papadopoulos, P.; Rosa-Neto, P.; Rochford, J.; Hamel, E. Pioglitazone Improves Reversal Learning and Exerts Mixed Cerebrovascular Effects in a Mouse Model of Alzheimer’s Disease with Combined Amyloid-β and Cerebrovascular Pathology. PLoS One 2013, 8 (7), e68612, DOI: 10.1371/journal.pone.0068612[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1WmtL7E&md5=fce388f68d0ca9c987ba06ea9172aa10Pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer's disease with combined amyloid-β and cerebrovascular pathologyPapadopoulos, Panayiota; Rosa-Neto, Pedro; Rochford, Joseph; Hamel, EdithPLoS One (2013), 8 (7), e68612CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Animal models of Alzheimer's disease (AD) are invaluable in dissecting the pathogenic mechanisms and assessing the efficacy of potential new therapies. Here, we used the peroxisome proliferator-activated receptor gamma agonist pioglitazone in an attempt to rescue the pathogenic phenotype in adult (12 mo) and aged (>18 mo) bitransgenic A/T mice that overexpress a mutated human amyloid precursor protein (APPSwe,Ind) and a constitutively active form of transforming growth factor-β1 (TGF-β1). A/T mice recapitulate the AD-related cognitive deficits, amyloid beta (Aβ) and cerebrovascular pathologies, as well as the altered metabolic and vascular coupling responses to increased neuronal activity. Pioglitazone normalized neurometabolic and neurovascular coupling responses to sensory stimulation, and reduced cortical astroglial and hippocampal microglial activation in both age groups. Spatial learning and memory deficits in the Morris water maze were not rescued by pioglitazone, but reversal learning was improved in the adult cohort notwithstanding a progressing Aβ pathol. While pioglitazone preserved the constitutive nitric oxide synthesis in the vessel wall, it unexpectedly failed to restore cerebrovascular reactivity in A/T mice and even exacerbated the dilatory deficits. These data demonstrate pioglitazone's efficacy on selective AD hallmarks in a complex AD mouse model of comorbid amyloidosis and cerebrovascular pathol. They further suggest a potential benefit of pioglitazone in managing neuroinflammation, cerebral perfusion and glucose metab. in AD patients devoid of cerebrovascular pathol.
- 54Prakash, A.; Kumar, A. Role of Nuclear Receptor on Regulation of BDNF and Neuroinflammation in Hippocampus of β-Amyloid Animal Model of Alzheimer’s Disease. Neurotoxic. Res. 2014, 25 (5), 335– 347, DOI: 10.1007/s12640-013-9437-9[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXls12qsrk%253D&md5=54ca948f8ec0066c16c42dd0015f1e04Role of Nuclear Receptor on Regulation of BDNF and Neuroinflammation in Hippocampus of β-Amyloid Animal Model of Alzheimer's DiseasePrakash, Atish; Kumar, AnilNeurotoxicity Research (2014), 25 (4), 335-347CODEN: NURRFI; ISSN:1029-8428. (Springer)Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have been reported to provide neuroprotective effects against neurodegenerative diseases. The current study was carried out to investigate the effects of chronic administration of pioglitazone, a PPAR-γ agonist, on cognitive impairment in an animal model of Alzheimer's disease induced by β-amyloid. Wistar rats received intracerebroventricular (ICV) β-amyloid (βA) application (3 nmol/3 μL), and behavioral alterations (locomotor activity and memory performance) were assessed. Animals were sacrificed immediately following the last behavioral session, and their brains were removed and dissected. Mitochondrial enzymes, oxidative parameters, inflammatory mediators (TNF-α, IL-6), caspase activity, and BDNF levels were measured in the hippocampus. ICV βA-treated rats showed a memory deficit and significantly decreased BDNF level, simultaneously, increase in mitochondrial oxidative damage and inflammatory mediators in the hippocampus. Memory impairment and oxidative damage were reversed by administration of pioglitazone (15 and 30 mg/kg). Pioglitazone also significantly restored the BDNF level and attenuated the actions of inflammatory markers in ICV βA-treated rats. However, pretreatment with PPAR-γ antagonist BADGE (15 mg/kg) with higher dose of pioglitazone significantly reversed its protective action in memory impairment in βA-treated rats, which indicates the involvement of PPAR-γ receptors mediating neuroprotective action. These results demonstrate that pioglitazone offers protection against β-amyloid-induced memory dysfunction possibly due to its antioxidant, anti-inflammatory, anti-apoptotic action and neurogenesis-like effect therefore, could have a therapeutic potential in Alzheimer's disease.
- 55Hamano, T.; Shirafuji, N.; Makino, C.; Yen, S.-H.; Kanaan, N. M.; Ueno, A.; Suzuki, J.; Ikawa, M.; Matsunaga, A.; Yamamura, O.; Kuriyama, M.; Nakamoto, Y. Pioglitazone Prevents Tau Oligomerization. Biochem. Biophys. Res. Commun. 2016, 478 (3), 1035– 1042, DOI: 10.1016/j.bbrc.2016.08.016[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVWmsb%252FP&md5=f81bd55b047a6ad500b9d0ca9f391668Pioglitazone prevents tau oligomerizationHamano, Tadanori; Shirafuji, Norimichi; Makino, Chiemi; Yen, Shu-Hui; Kanaan, Nicholas M.; Ueno, Asako; Suzuki, Jinya; Ikawa, Masamichi; Matsunaga, Akiko; Yamamura, Osamu; Kuriyama, Masaru; Nakamoto, YasunariBiochemical and Biophysical Research Communications (2016), 478 (3), 1035-1042CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Tau aggregation and amyloid β protein (Aβ) deposition are the main causes of Alzheimer's disease (AD). Peroxisome proliferator-activated receptor γ (PPARγ) activation modulates Aβ prodn. To test whether the PPARγ agonist pioglitazone (PIO) is also effective in preventing tau aggregation in AD, we used a cellular model in which wild-type tau protein (4R0N) is overexpressed (M1C cells) (Hamano et al., 2012) as well as primary neuronal cultures. PIO reduced both phosphorylated and total tau levels, and inactivated glycogen synthase kinase 3β, a major tau kinase, assocd. with activation of Akt. In addn., PIO decreased cleaved caspase3 and C-terminal truncated tau species by caspase, which is expected to decrease tau aggregation. A fractionation study showed that PIO reduced high mol.-wt. (120 kDa), oligomeric tau species in Tris Insol., sarkosyl-sol. fractions. Tau decrease was reversed by adding GW9662, a PPARγ antagonist. Together, our current results support the idea that PPARγ agonists may be useful therapeutic agents for AD.
- 56Cho, D.-H.; Lee, E. J.; Kwon, K. J.; Shin, C. Y.; Song, K.-H.; Park, J.-H.; Jo, I.; Han, S.-H. Troglitazone, a Thiazolidinedione, Decreases Tau Phosphorylation through the Inhibition of Cyclin-Dependent Kinase 5 Activity in SH-SY5Y Neuroblastoma Cells and Primary Neurons. J. Neurochem. 2013, 126 (5), 685– 695, DOI: 10.1111/jnc.12264[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlSqu77E&md5=bc41a6c9ecae5a8ab3982eecd77b09bbTroglitazone, a thiazolidinedione, decreases tau phosphorylation through the inhibition of cyclin-dependent kinase 5 activity in SH-SY5Y neuroblastoma cells and primary neuronsCho, Du-Hyong; Lee, Eun Joo; Kwon, Kyoung Ja; Shin, Chan Young; Song, Kee-Ho; Park, Jung-Hyun; Jo, Inho; Han, Seol-HeuiJournal of Neurochemistry (2013), 126 (5&6), 685-695CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)The peroxisome proliferator-activated receptor gamma (PPARγ) agonists thiazolidinediones (TZDs) are prescribed for the treatment of type 2 diabetes mellitus. Furthermore, it has been reported that TZDs have a beneficial effect on neurodegenerative disorders, such as Alzheimer's disease. However, the mol. mechanisms underlying this effect are not fully understood. Here, we investigated whether and how troglitazone, a parent TZD drug, inhibits tau phosphorylation. Treatment with troglitazone decreased tau-Thr231 phosphorylation and p35, the specific activator of cyclin-dependent kinase 5 (CDK5), in a dose- and time-dependent manner. Troglitazone also decreased CDK5 enzymic activity, and ectopic expression of p25, the cleaved and more active form of p35, restored the troglitazone-induced decrease in tau-Thr231 phosphorylation. Treatment with either MG-132, a reversible proteasome inhibitor, or lactacystin, a specific and irreversible 26S proteasome inhibitor, significantly reversed the obsd. inhibitory effects of troglitazone. However, GW9662, a specific and irreversible PPARγ antagonist, did not alter the obsd. inhibitory effects. Similar results were also found when other TZD drugs, pioglitazone and rosiglitazone, were used. Treatment with various inhibitors revealed that troglitazone-induced inhibitions of tau-Thr231 phosphorylation and p35 expression were not mediated by glycogen synthase kinase 3β, protein kinase A, and protein phosphatase 2A signaling pathways. Finally, we also found that the same obsd. inhibitory effects of troglitazone hold true for the use of primary cortical neurons. Taken together, we demonstrated that TZDs repressed tau-Thr231 phosphorylation via the inhibition of CDK5 activity, which was mediated by the proteasomal degrdn. of p35 and a PPARγ-independent signaling pathway. Thiazolidinediones (TZDs) decrease tau-Thr231 phosphorylation via the inhibition of CDK5 enzymic activity, which is mediated by the enhanced proteasomal degrdn. of p35 and a PPARγ-independent signaling pathway. This mol. mechanism implies a role for TZD drugs in the prevention and treatment of Alzheimer's disease.
- 57Harrington, C.; Sawchak, S.; Chiang, C.; Davies, J.; Donovan, C.; Saunders, A. M.; Irizarry, M.; Jeter, B.; Zvartau-Hind, M.; H. van Dyck, C.; Gold, M. Rosiglitazone Does Not Improve Cognition or Global Function When Used as Adjunctive Therapy to AChE Inhibitors in Mild-to-Moderate Alzheimers Disease: Two Phase 3 Studies. Curr. Alzheimer Res. 2011, 8 (5), 592– 606, DOI: 10.2174/156720511796391935[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsl2qtrw%253D&md5=54516c366701851a6d1745fc07969108Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studiesHarrington, C.; Sawchak, S.; Chiang, C.; Davies, J.; Donovan, C.; Saunders, A. M.; Irizarry, M.; Jeter, B.; Zvartau-Hind, M.; van Dyck, C. H.; Gold, M.Current Alzheimer Research (2011), 8 (5), 592-606CODEN: CARUBY; ISSN:1567-2050. (Bentham Science Publishers Ltd.)Introduction: Two phase 3 studies evaluated the efficacy and safety of rosiglitazone (RSG), a type 2 diabetes treatment, in an extended release (RSG XR) form as adjunctive therapy to ongoing acetylcholine esterase inhibitor (AChEI) treatment in AD (REFLECT-2, adjunctive to donepezil; REFLECT-3, to any AChEI). An open-label extension study (REFLECT-4) assessed RSG XR long-term safety. Methods: In these two double-blind, placebo-controlled studies, subjects with mild-to-moderate probable AD were randomized within 2 apolipoprotein E (APOE) allelic strata (APOE ε4-pos., APOE ε4-neg.) to once daily placebo, 2 mg RSG XR, or 8 mg RSG XR for 48 wk (REFLECT-2, N = 1,496; REFLECT-3, N = 1,485). Co-primary efficacy endpoints were change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Clin. Dementia Rating scale - Sum of Boxes (CDR-SB) scores at week 48. Three populations were analyzed: APOE4-neg., all subjects except APOE ε4 homozygotes, and the full intent-to-treat population. Results: No statistically or clin. relevant differences between treatment groups were obsd. on the a priori primary endpoints in REFLECT-2 or REFLECT-3. Edema was the most frequent adverse event with RSG in each study (14% and 19%, resp., at 8 mg RSG XR). Conclusions: No evidence of statistically or clin. significant efficacy in cognition or global function was detected for 2 mg or 8 mg RSG XR as adjunctive therapy to ongoing AChEIs. There was no evidence of an interaction between treatment and APOE status. Safety and tolerability of RSG XR was consistent with the known profile of rosiglitazone.
- 58Gold, M.; Alderton, C.; Zvartau-Hind, M.; Egginton, S.; Saunders, A. M.; Irizarry, M.; Craft, S.; Landreth, G.; Linnamägi, Ü.; Sawchak, S. Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer’s Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III Study. Dementia Geriatr. Cognit. Disord. 2010, 30 (2), 131– 146, DOI: 10.1159/000318845[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1agsrjM&md5=22e08bf51f12957b0f1508fdef931470Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer's Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III StudyGold, Michael; Alderton, Claire; Zvartau-Hind, Marina; Egginton, Sally; Saunders, Ann M.; Irizarry, Michael; Craft, Suzanne; Landreth, Gary; Linnamaegi, Uella; Sawchak, SharonDementia and Geriatric Cognitive Disorders (2010), 30 (2), 131-146CODEN: DGCDFX; ISSN:1420-8008. (S. Karger AG)A phase II study of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer's disease (AD) detected a treatment benefit to cognition in apolipoprotein E(APOE)-ε4-neg. subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR. This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (ε4-pos., ε4-neg.), subjects were randomized (2:2:2:1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+). At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-ε4-neg. subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%). No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-ε4-neg. or other anal. populations. The safety and tolerability of RSG XR was consistent with its known pharmacol.
- 59Cheng, H.; Shang, Y.; Jiang, L.; Shi, T.-L.; Wang, L. The Peroxisome Proliferators Activated Receptor-Gamma Agonists as Therapeutics for the Treatment of Alzheimer’s Disease and Mild-to-Moderate Alzheimer’s Disease: A Meta-Analysis. Int. J. Neurosci. 2016, 126 (4), 299– 307, DOI: 10.3109/00207454.2015.1015722[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht12qsrw%253D&md5=78879ad4a62f4a65543c438a46228e11The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysisCheng, Huawei; Shang, Yuping; Jiang, Ling; Shi, Tian-lu; Wang, LinInternational Journal of Neuroscience (2016), 126 (4), 299-307CODEN: IJNUB7; ISSN:0020-7454. (Taylor & Francis Ltd.)Alzheimer's disease (AD) is a devastating neurodegenerative disease and there is no effective therapy for it. Peroxisome proliferators activated receptor-gamma (PPAR-γ) agonists is a promising therapeutic approach for AD and has been widely studied recently, but no consensus was available up to now. To clarify this point, a meta-anal. was performed. We searched MEDLINE, EMBASE, Cochrane Central database, PUBMED, Springer Link database, SDOS database, CBM, CNKI and Wan fang database by Dec. 2014. Standardized mean difference (SMD), relative risk (RR) and 95% confidence interval (CI) were calcd. to assess the strength of the novel therapeutics for AD and mild-to-moderate AD. A total of nine studies comprising 1314 patients and 1311 controls were included in the final meta-anal. We found the effect of PPAR-γ agonists on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) scores by using STATA software. There was no evidence for obvious publication bias in the overall meta-anal. There is insufficient evidence of statistically incognition of AD and mild-to-moderate AD patients have been improved who were treated with PPAR-γ agonists in our research. However, PPAR-γ agonists may be a promising therapeutic approach in future, esp. pioglitazone, with large-scale randomized controlled trials to confirm.
- 60Liu, J.; Wang, L.; Jia, J. Peroxisome Proliferator-Activated Receptor-Gamma Agonists for Alzheimer’s Disease and Amnestic Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. Drugs Aging 2015, 32 (1), 57– 65, DOI: 10.1007/s40266-014-0228-7[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitV2ntL3E&md5=bc3fcbb735e4ea8c63ec912d0ee4dfc1Peroxisome Proliferator-Activated Receptor-Gamma Agonists for Alzheimer's Disease and Amnestic Mild Cognitive Impairment: A Systematic Review and Meta-AnalysisLiu, Jia; Wang, Lu-ning; Jia, Jian-pingDrugs & Aging (2015), 32 (1), 57-65CODEN: DRAGE6; ISSN:1170-229X. (Springer International Publishing AG)Background: Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, and close assocns. between AD and diabetes have been found. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists, as newly-developed oral hypoglycemic agents, were evaluated as a possible therapy for AD. Aim: We systematically evaluated the efficacy and safety of PPAR-γ agonists in the treatment of AD and amnestic mild cognitive impairment (aMCI), the prodromal stage of AD. Methods: A search of the electronic databases PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure (until July 2014) was conducted, and included randomized controlled trials. Dichotomous data were expressed as risk ratios (RRs) with 95 % confidence intervals (CIs), and continuous data were expressed as mean differences (MD) with 95 % CIs. The results were pooled using a random-effects model. Results: Nine eligible studies were identified, with 4,327 participants. Using the Alzheimer's Disease Assessment Scale-Cognitive subscale, pioglitazone was found to be efficacious, esp. for patients with comorbid diabetes (MD -3.47, 95 % CI -4.40 to -2.54). Rosiglitazone was not efficacious, even for apolipoprotein E (APOE) ε4 non-carriers (MD -0.31, 95 % CI -1.12 to 0.51). There was no increase in any adverse events (AEs) or serious AEs compared with placebo. Peripheral edema was the most frequent AE related to PPAR-γ agonist treatment (RR 4.14, 95 % CI 2.37-7.23). Conclusions: There is insufficient evidence to support the use of rosiglitazone in aMCI and AD patients in order to improve cognitive performance. Nonetheless, the efficacy of pioglitazone seems to be promising, particularly for patients with comorbid diabetes, however this needs to be further confirmed by well-designed trials with large sample sizes. PPAR-γ agonists such as rosiglitazone and pioglitazone are generally well-tolerated in AD and aMCI patients.
- 61Breidert, T.; Callebert, J.; Heneka, M. T.; Landreth, G.; Launay, J. M.; Hirsch, E. C. Protective Action of the Peroxisome Proliferator-Activated Receptor-γ Agonist Pioglitazone in a Mouse Model of Parkinson’s Disease. J. Neurochem. 2002, 82 (3), 615– 624, DOI: 10.1046/j.1471-4159.2002.00990.x[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xmt1ejsLY%253D&md5=a22e5318aae06a24540500bf18daa09fProtective action of the peroxisome proliferator-activated receptor-γ agonist pioglitazone in a mouse model of Parkinson's diseaseBreidert, T.; Callebert, J.; Heneka, M. T.; Landreth, G.; Launay, J. M.; Hirsch, E. C.Journal of Neurochemistry (2002), 82 (3), 615-624CODEN: JONRA9; ISSN:0022-3042. (Blackwell Science Ltd.)We examd. the effect of pioglitazone, a peroxisome proliferator-activated receptor-γ (PPARγ) agonist of the thiazolidinedione class, on dopaminergic nerve cell death and glial activation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. The acute intoxication of C57BL/6 mice with MPTP led to nigrostriatal injury, as detd. by tyrosine hydroxylase (TH) immunocytochem., and HPLC detection of striatal dopamine and metabolites. Damage to the nigrostriatal dopamine system was accompanied by a transient activation of microglia, as detd. by macrophage antigen-1 (Mac-1) and inducible nitric oxide synthase (iNOS) immunoreactivity, and a prolonged astrocytic response. Orally administered pioglitazone (∼ 20 mg/kg/day) attenuated the MPTP-induced glial activation and prevented the dopaminergic cell loss in the substantia nigra pars compacta (SNpc). In contrast, there was little redn. of MPTP-induced dopamine depletion, with no detectable effect on loss of TH immunoreactivity and glial response in the striatum of pioglitazone-treated animals. Low levels of PPARγ expression were detected in the ventral mesencephalon and striatum, and were unaffected by MPTP or pioglitazone treatment. Since pioglitazone affects primarily the SNpc in our model, different PPARγ-independent mechanisms may regulate glial activation in the dopaminergic terminals compared with the dopaminergic cell bodies after acute MPTP intoxication.
- 62Quinn, L. P.; Crook, B.; Hows, M. E.; Vidgeon-Hart, M.; Chapman, H.; Upton, N.; Medhurst, A. D.; Virley, D. J. The PPARγ Agonist Pioglitazone Is Effective in the MPTP Mouse Model of Parkinson’s Disease through Inhibition of Monoamine Oxidase B. Br. J. Pharmacol. 2008, 154 (1), 226– 233, DOI: 10.1038/bjp.2008.78[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXltFOqs7k%253D&md5=26608de37ec831814c50f23b1baa2b68The PPARγ agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase BQuinn, L. P.; Crook, B.; Hows, M. E.; Vidgeon-Hart, M.; Chapman, H.; Upton, N.; Medhurst, A. D.; Virley, D. J.British Journal of Pharmacology (2008), 154 (1), 226-233CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)The peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone has previously been shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease, an effect attributed to its anti-inflammatory properties. In the present investigation, we provide evidence that pioglitazone is effective in the MPTP mouse model, not via an anti-inflammatory action, but through inhibition of MAO-B, the enzyme required to biotransform MPTP to its active neurotoxic metabolite 1-methyl-4-phenylpyridinium (MPP+). Exptl. approach: Mice were treated with pioglitazone (20 mg kg-1 b.i.d. (twice a day), p.o., for 7 days), prior and post or post-MPTP (30 mg kg-1 s.c.) treatment. Mice were then assessed for motor impairments on a beam-walking app. and for redns. in TH immunoreactivity in the substantia nigra and depletions in striatal dopamine. The effects of pioglitazone on striatal MPP+ levels and MAO-B activity were also assessed. Mice treated with MPTP showed deficits in motor performance, marked depletions in striatal dopamine levels and a concomitant redn. in TH immunoreactivity in the substantia nigra. Pretreatment with pioglitazone completely prevented these effects of MPTP. However, pretreatment with pioglitazone also significantly inhibited the MPTP-induced prodn. of striatal MPP+ and the activity of MAO-B in the striatum. The neuroprotection obsd. with pioglitazone pretreatment in the MPTP mouse model was due to the blockade of the conversion of MPTP to its active toxic metabolite MPP+, via inhibition of MAO-B. Published online 10 March 2008.
- 63Pisanu, A.; Lecca, D.; Mulas, G.; Wardas, J.; Simbula, G.; Spiga, S.; Carta, A. R. Dynamic Changes in Pro-and Anti-Inflammatory Cytokines in Microglia after PPAR-γ Agonist Neuroprotective Treatment in the MPTPp Mouse Model of Progressive Parkinson’s Disease. Neurobiol. Dis. 2014, 71, 280– 291, DOI: 10.1016/j.nbd.2014.08.011[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVSqt73F&md5=5d178467ad1349b135b7328726844d92Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson's diseasePisanu, Augusta; Lecca, Daniela; Mulas, Giovanna; Wardas, Jadwiga; Simbula, Gabriella; Spiga, Saturnino; Carta, Anna R.Neurobiology of Disease (2014), 71 (), 280-291CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)Neuroinflammatory changes play a pivotal role in the progression of Parkinson's disease (PD) pathogenesis. Recent findings have suggested that activated microglia may polarize similarly to peripheral macrophages in the central nervous system (CNS), assuming a pro-inflammatory M1 phenotype or the alternative anti-inflammatory M2 phenotype via cytokine prodn. A skewed M1 activation over M2 has been related to disease progression in Alzheimer disease, and modulation of microglia polarization may be a therapeutic target for neuroprotection. By using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-probenecid (MPTPp) mouse model of progressive PD, we investigated dynamic changes in the prodn. of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and anti-inflammatory cytokines, such as transforming growth factor (TGF)-β and IL-10, within Iba-1-pos. cells in the substantia nigra compacta (SNc). In addn., to further characterize changes in the M2 phenotype, we measured CD206 in microglia. Moreover, in order to target microglia polarization, we evaluated the effect of the peroxisome-proliferator-activated receptor (PPAR)-γ agonist rosiglitazone, which has been shown to exert neuroprotective effects on nigral dopaminergic neurons in PD models, and acts as a modulator of cytokine prodn. and phenotype in peripheral macrophages.Chronic treatment with MPTPp induced a progressive degeneration of SNc neurons. The neurotoxin treatment was assocd. with a gradual increase in both TNF-α and IL-1β colocalization with Iba-1-pos. cells, suggesting an increase in pro-inflammatory microglia. In contrast, TGF-β colocalization was reduced by the neurotoxin treatment, while IL-10 was mostly unchanged. Administration of rosiglitazone during the full duration of MPTPp treatment reverted both TNF-α and IL-1β colocalization with Iba-1 to control levels. Moreover, rosiglitazone induced an increase in TGF-β and IL-10 colocalization compared with the MPTPp treatment. CD206 was gradually reduced by the chronic MPTPp treatment, while rosiglitazone restored control levels, suggesting that M2 anti-inflammatory microglia were stimulated and inflammatory microglia were inhibited by the neuroprotective treatment. The results show that the dopaminergic degeneration was assocd. with a gradual microglia polarization to the inflammatory over the anti-inflammatory phenotype in a chronic mouse model of PD. Neuroprotective treatment with rosiglitazone modulated microglia polarization, boosting the M2 over the pro-inflammatory phenotype. PPAR-γ agonists may offer a novel approach to neuroprotection, acting as disease-modifying drugs through an immunomodulatory action in the CNS.
- 64Swanson, C. R.; Joers, V.; Bondarenko, V.; Brunner, K.; Simmons, H. A.; Ziegler, T. E.; Kemnitz, J. W.; Johnson, J. A.; Emborg, M. E. The PPAR-γ Agonist Pioglitazone Modulates Inflammation and Induces Neuroprotection in Parkinsonian Monkeys. J. Neuroinflammation 2011, 8, 91, DOI: 10.1186/1742-2094-8-91[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFegsbfP&md5=3cdee6c1179c23c2d7b4976e41a416a4The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeysSwanson, Christine R.; Joers, Valerie; Bondarenko, Viktoriya; Brunner, Kevin; Simmons, Heather A.; Ziegler, Toni E.; Kemnitz, Joseph W.; Johnson, Jeffrey A.; Emborg, Marina E.Journal of Neuroinflammation (2011), 8 (), 91CODEN: JNOEB3; ISSN:1742-2094. (BioMed Central Ltd.)Background: Activation of the peroxisome proliferator-activated receptor gamma (PPAR-γ) has been proposed as a possible neuroprotective strategy to slow down the progression of early Parkinson's disease (PD). Here we report preclin. data on the use of the PPAR-γ agonist pioglitazone (Actos; Takeda Pharmaceuticals Ltd.) in a paradigm resembling early PD in nonhuman primates. Methods: Rhesus monkeys that were trained to perform a battery of behavioral tests received a single intracarotid arterial injection of 20 mL of saline contg. 3 mg of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Twenty-four hours later the monkeys were assessed using a clin. rating scale, matched accordingly to disability, randomly assigned to one of three groups [placebo (n = 5), 2.5 (n = 6) or 5 (n = 5) mg/kg of pioglitazone] and their treatments started. Three months after daily oral dosing, the animals were necropsied. Results: We obsd. significant improvements in clin. rating score (P = 0.02) in the animals treated with 5 mg/kg compared to placebo. Behavioral recovery was assocd. with preservation of nigrostriatal dopaminergic markers, obsd. as higher tyrosine hydroxylase (TH) putaminal optical d. (P = 0.011), higher stereol. cell counts of TH-ir (P = 0.02) and vesicular monoamine transporter-2 (VMAT-2)-ir nigral neurons (P = 0.006). Stereol. cell counts of Nissl-stained nigral neurons confirmed neuroprotection (P = 0.017). Pioglitazone-treated monkeys also showed a dose-dependent modulation of CD68-ir inflammatory cells, that was significantly decreased for 5 mg/kg treated animals compared to placebo (P = 0.018). A sep. expt. to assess CSF penetration of pioglitazone revealed that 5 mg/kg p.o. induced consistently higher levels than 2.5 mg/kg and 7.5 mg/kg. p.o. Conclusions: Our results indicate that oral administration of pioglitazone is neuroprotective when administered early after inducing a parkinsonian syndrome in rhesus monkeys and supports the concept that PPAR-γ is a viable target against neurodegeneration.
- 65Pinto, M.; Nissanka, N.; Peralta, S.; Brambilla, R.; Diaz, F.; Moraes, C. T. Pioglitazone Ameliorates the Phenotype of a Novel Parkinson’s Disease Mouse Model by Reducing Neuroinflammation. Mol. Neurodegener. 2016, 11, 25, DOI: 10.1186/s13024-016-0090-7[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjtVOqt7w%253D&md5=ef35f48cf4aff1882580062baf8227e2Pioglitazone ameliorates the phenotype of a novel Parkinson's disease mouse model by reducing neuroinflammationPinto, Milena; Nissanka, Nadee; Peralta, Susana; Brambilla, Roberta; Diaz, Francisca; Moraes, Carlos T.Molecular Neurodegeneration (2016), 11 (), 25/1-25/15CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The cause of the motor symptoms is the loss of dopaminergic neurons in the substantia nigra with consequent depletion of dopamine in the striatum. Although the etiol. of PD is unknown, mitochondrial dysfunctions, including cytochrome c oxidase (Complex IV) impairment in dopaminergic neurons, have been assocd. with the disease's pathophysiol. In order to analyze the role of Complex IV in PD, we knocked out Cox10 (essential for the maturation of COXI, a catalytic subunit of Complex IV) in dopaminergic neurons. We also tested whether the resulting phenotype was improved by stimulating the PPAR-γ pathway. Results:Cox10/DAT-cre mice showed decreased nos. of TH+ and DAT+ cells in the substantia nigra, early striatal dopamine depletion, motor defects reversible with L-DOPA treatment and hypersensitivity to L-DOPA with hyperkinetic behavior. We found that chronic pioglitazone (PPAR-γ agonist) treatment ameliorated the motor phenotype in Cox10/DAT-cre mice. Although neither mitochondrial function nor the no. of dopaminergic neurons was improved, neuroinflammation in the midbrain and the striatum was decreased. Conclusions: By triggering a mitochondrial Complex IV defect in dopaminergic neurons, we created a new mouse model resembling the late stages of PD with massive degeneration of dopaminergic neurons and striatal dopamine depletion. The motor phenotypes were improved by Pioglitazone treatment, suggesting that targetable secondary pathways can influence the development of certain forms of PD.
- 66Lecca, D.; Nevin, D. K.; Mulas, G.; Casu, M. A.; Diana, A.; Rossi, D.; Sacchetti, G.; Carta, A. R. Neuroprotective and Anti-Inflammatory Properties of a Novel Non-Thiazolidinedione PPARγ Agonist in Vitro and in MPTP-Treated Mice. Neuroscience 2015, 302, 23– 35, DOI: 10.1016/j.neuroscience.2015.04.026[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXntlWmsLY%253D&md5=a575391f7368c514c35c14866f405e56Neuroprotective and anti-inflammatory properties of a novel non-thiazolidinedione PPARγ agonist in vitro and in MPTP-treated miceLecca, D.; Nevin, D. K.; Mulas, G.; Casu, M. A.; Diana, A.; Rossi, D.; Sacchetti, G.; Carta, A. R.Neuroscience (Amsterdam, Netherlands) (2015), 302 (), 23-35CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)Peroxisome proliferator-activated receptor (PPAR)γ is a potential pharmacol. target for disease-modification in Parkinson's disease (PD), mainly acting by modulating the neuroinflammatory response. However, currently available agonists thiazolidinediones (TZDs) present limitations due to safety concerns. We evaluated a novel thiobarbituric-like compd. MDG548, which acts as a functional PPARγ agonist displaying higher and selective binding affinity as compared to TZDs. Neuroprotection by MDG548 was tested in vitro and in a mouse MPTP model of PD, and neuroinflammation was investigated as a putative underlying mechanism. Viability assay on rat cortical neurons showed lack of cytotoxic effect in the dose-range of 100 nM-10 μM, which was therefore used for testing in vitro protection against H2O2 and MPP+ neurotoxicity. MDG548 dose-dependently increased cell viability of rat cortical neurons co-treated with H2O2 or pre-exposed to MDG548 prior to H2O2. Moreover, MDG548 induced neuroprotection in MPP+-treated PC12 cells. NF-kB activation was investigated to assess anti-inflammatory activity. MDG548 dose-dependently decreased NF-kB activation induced by LPS (100 ng/100 mL) in HEK-Blue-hTLR4 cells. Given the supposed cancer risk of other PPARγ agonists, Ames test for genotoxicity was performed in Salmonella typhimurium TA100 and TA98 strains, showing that MDG548 was not genotoxic. In vivo, BL/6J mice were treated with MPTP (20 mg/kg i.p. once/day for 4 days) in assocn. with saline or MDG548 (2, 5, 10 mg/kg i.p.). Stereol. counting showed that MDG548 prevented the MPTP-induced redn. in TH-pos. cells in the substantia nigra compacta (SNc) at all doses tested. Moreover, MDG548 reduced reactive microglia and iNOS induction in the SNc. MDG548, being a non-TZD compd. with high PPARγ affinity, void of genotoxicity, and with in vitro as well as in vivo neuroprotective properties, provides a promising alternative in the search for safer PPARγ agonists to be tested as potential disease-modifying drugs in PD.
- 67Lecca, D.; Janda, E.; Mulas, G.; Diana, A.; Martino, C.; Angius, F.; Spolitu, S.; Casu, M. A.; Simbula, G.; Boi, L.; Batetta, B.; Spiga, S.; Carta, A. R. Boosting Phagocytosis and Anti-Inflammatory Phenotype in Microglia Mediates Neuroprotection by PPARγ Agonist MDG548 in Parkinson’s Disease Models. Br. J. Pharmacol. 2018, 175 (16), 3298– 3314, DOI: 10.1111/bph.14214[Crossref], [PubMed], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlSlur3N&md5=0082c9b67fbc756ae2bf83ee2024a6a0Boosting phagocytosis and anti-inflammatory phenotype in microglia mediates neuroprotection by PPARγ agonist MDG548 in Parkinson's disease modelsLecca, Daniela; Janda, Elzbieta; Mulas, Giovanna; Diana, Andrea; Martino, Concetta; Angius, Fabrizio; Spolitu, Stefano; Casu, Maria Antonietta; Simbula, Gabriella; Boi, Laura; Batetta, Barbara; Spiga, Saturnino; Carta, Anna R.British Journal of Pharmacology (2018), 175 (16), 3298-3314CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)Background and Purpose : Microglial phenotype and phagocytic activity are deregulated in Parkinson's disease (PD). PPARγ agonists are neuroprotective in exptl. PD, but their role in regulating microglial phenotype and phagocytosis has been poorly investigated. We addressed it by using the PPARγ agonist MDG548. Exptl. Approach : Murine microglial cell line MMGT12 was stimulated with LPS and/or MDG548, and their effect on phagocytosis of fluorescent microspheres or necrotic neurons was investigated by flow cytometry. Cytokines and markers of microglia phenotype, such as mannose receptor C type 1; MRC1 ,Ym1, CD68 were measured by eLisa and fluorescent immunohistochem. Levels of Beclin-1, which plays a role in microglial phagocytosis, were measured by Western blotting. In the in vivo MPTP-probenecid (MPTPp) model of PD in mice, MDG548 was tested on motor impairment, nigral neurodegeneration, microglial activation and phenotype. Chronic MPTPp treatment in mice down-regulated MRC1 and TGF-β and up-regulated TNF-α and IL-1β immunoreactivity in activated CD11b-pos. microglia, causing the death of nigral dopaminergic neurons. MDG548 arrested MPTPp-induced cell death, enhanced MRC1 and restored cytokine levels. Conclusions and Implications : This study adds a novel mechanism for PPARγ-mediated neuroprotection in PD and suggests that increasing phagocytic activity and anti-inflammatory markers may represent an effective disease-modifying approach.
- 68Swanson, C. R.; Du, E.; Johnson, D. A.; Johnson, J. A.; Emborg, M. E. Neuroprotective Properties of a Novel Non-Thiazoledinedione Partial PPAR-γ Agonist against MPTP. PPAR Res. 2013, 2013, 582809 DOI: 10.1155/2013/582809[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c7mtVamtA%253D%253D&md5=a426792c4fac2dc9f5595a986bb7f0f7Neuroprotective Properties of a Novel Non-Thiazoledinedione Partial PPAR- γ Agonist against MPTPSwanson Christine R; Du Eric; Johnson Delinda A; Johnson Jeffrey A; Emborg Marina EPPAR research (2013), 2013 (), 582809 ISSN:1687-4757.Activation of the peroxisome proliferator activated receptor-gamma (PPAR)- γ is proposed as a neuroprotective strategy to treat neurodegenerative disorders. In this study, we examined if LSN862 (LSN), a novel non-thiazoledinedione partial PPAR- γ agonist, was neuroprotective in a mouse model of Parkinson's disease (PD) and assessed possible mechanisms of action. LSN (3, 10, or 30 mg/kg) or vehicle was orally administered daily to C57BL/6 and antioxidant response element-human placental alkaline phosphatase (ARE-hPAP) reporter mice 3 days prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg, i.p. × 5 days) or PBS administration. LSN elicited a dose-dependent preservation of dopaminergic nigrostriatal innervation that was not associated with inhibition of MPTP metabolism or activation of Nrf2-ARE, although changes in NQO1 and SOD2 mRNA were observed. A significant dose-dependent downregulation in MAC-1 and GFAP positive cells was observed in MPTP + LSN-treated mice as well as significant downregulation of mRNA expression levels of these inflammatory markers. MPTP-induced increases in PPAR- γ and PGC1 α expression were ameliorated by LSN dosing. Our results demonstrate that oral administration of LSN is neuroprotective against MPTP-induced neurodegeneration, and this effect is associated with downregulation of neuroinflammation, decreased oxidative stress, and modulation of PPAR- γ and PGC1 α expression. These results suggest that LSN can be a candidate alternative non-thiazoledinedione partial PPAR- γ agonist for neuroprotective treatment of PD.
- 69Das, N. R.; Gangwal, R. P.; Damre, M. V.; Sangamwar, A. T.; Sharma, S. S. A PPAR-β/δ Agonist Is Neuroprotective and Decreases Cognitive Impairment in a Rodent Model of Parkinson’s Disease. Curr. Neurovasc. Res. 2014, 11 (2), 114– 124, DOI: 10.2174/1567202611666140318114037[Crossref], [PubMed], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXos1Ghurs%253D&md5=193337c81e37443c0771b819764cb85cA PPAR-β/δ Agonist is Neuroprotective and Decreases Cognitive Impairment in a Rodent Model of Parkinsonμs DiseaseDas, Nihar R.; Gangwal, Rahul P.; Damre, Mangesh V.; Sangamwar, Abhay T.; Sharma, Shyam S.Current Neurovascular Research (2014), 11 (2), 114-124CODEN: CNRUAM; ISSN:1875-5739. (Bentham Science Publishers Ltd.)Parkinson's disease (PD) is assocd. with higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of GW0742, a PPAR-β/δ agonist in rat model of cognitive impairment assocd. with PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) (100 μg/1 μl/side) produced significant cognitive dysfunctions. PPAR-β/δ agonist GW0742 at a dose of 30 and 100 μg/kg showed significant improvement in cognitive impairments caused by MPTP in rat model of PD as evident from passive avoidance and Morris water maze test. MPTP-induced massive oxidative damage and DNA fragmentation was ameliorated by GW0742 treatment as obsd. after MDA and GSH estn. and TUNEL assay. Tyrosine hydroxylase pos. neurons were decreased by 25% of normal control in MPTP group and GW0742 treatment restored tyrosine hydroxylase levels showing neuroprotective nature. Further, we performed physiol. based pharmacokinetic (PBPK) modeling study using GastroPlus to characterize the kinetics of GW0742 in the brain. The predicted amts. of GW0742 in brain suggest that it has the ability to cross the blood brain barrier. This study implicates the involvement of PPAR-β/δ in PD induced cognitive impairment.
- 70Uppalapati, D.; Das, N. R.; Gangwal, R. P.; Damre, M. V.; Sangamwar, A. T.; Sharma, S. S. Neuroprotective Potential of Peroxisome Proliferator Activated Receptor-α Agonist in Cognitive Impairment in Parkinson’s Disease: Behavioral, Biochemical, and PBPK Profile. PPAR Res. 2014, 2014, 753587, DOI: 10.1155/2014/753587[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crpvVKhtQ%253D%253D&md5=bf33ee81cecd6f594784b09d52e459e2Neuroprotective Potential of Peroxisome Proliferator Activated Receptor- α Agonist in Cognitive Impairment in Parkinson's Disease: Behavioral, Biochemical, and PBPK ProfileUppalapati Dedeepya; Das Nihar R; Sharma Shyam S; Gangwal Rahul P; Damre Mangesh V; Sangamwar Abhay TPPAR research (2014), 2014 (), 753587 ISSN:1687-4757.Parkinson's disease (PD) is a common neurodegenerative disorder affecting 1% of the population by the age of 65 years and 4-5% of the population by the age of 85 years. PD affects functional capabilities of the patient by producing motor symptoms and nonmotor symptoms. Apart from this, it is also associated with a higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of fenofibrate, a PPAR- α agonist in cognitive impairment model in PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (100 μg/1 μL/side) produced significant cognitive dysfunctions. Fenofibrate treatment at 10, 30, and 100 mg/kg for twenty-five days was found to be neuroprotective and improved cognitive impairment in MPTP-induced PD model as evident from behavioral, biochemical (MDA, GSH, TNF- α , and IL-6), immunohistochemistry (TH), and DNA fragmentation (TUNEL positive cells) studies. Further, physiologically based pharmacokinetic (PBPK) modeling study was performed using GastroPlus to characterize the kinetics of fenofibric acid in the brain. A good agreement was found between pharmacokinetic parameters obtained from the actual and simulated plasma concentration-time profiles of fenofibric acid. Results of this study suggest that PPAR- α agonist (fenofibrate) is neuroprotective in PD-induced cognitive impairment.
- 71Barbiero, J. K.; Santiago, R.; Tonin, F. S.; Boschen, S.; Da Silva, L. M.; De Paula Werner, M. F.; Da Cunha, C.; Lima, M. M. S.; Vital, M. A. B. F. PPAR-α Agonist Fenofibrate Protects against the Damaging Effects of MPTP in a Rat Model of Parkinson’s Disease. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2014, 53, 35– 44, DOI: 10.1016/j.pnpbp.2014.02.009[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpvFSrtb4%253D&md5=38fef16150ee1a1256328d105b6b2d21PPAR-α agonist fenofibrate protects against the damaging effects of MPTP in a rat model of Parkinson's diseaseBarbiero, Janaina K.; Santiago, Ronise; Tonin, Fernanda S.; Boschen, Suelen; da Silva, Luisa Mota; de Paula Werner, Maria Fernanda; da Cunha, Claudio; Lima, Marcelo M. S.; Vital, Maria A. B. F.Progress in Neuro-Psychopharmacology & Biological Psychiatry (2014), 53 (), 35-44CODEN: PNPPD7; ISSN:0278-5846. (Elsevier Inc.)Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The etiol. and pathogenesis of PD are still unknown, however, many evidences suggest a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction. The peroxisome proliferator-activated receptor (PPAR) ligands, a member of the nuclear receptor family, have anti-inflammatory activity over a variety of rodent's models for acute and chronic inflammation. PPAR-α agonists, a subtype of the PPAR receptors, such as fenofibrate, have been shown a major role in the regulation of inflammatory processes. Animal models of PD have shown that neuroinflammation is one of the most important mechanisms involved in dopaminergic cell death. In addn., anti-inflammatory drugs are able to attenuate toxin-induced parkinsonism. In this study we evaluated the effects of oral administration of fenofibrate 100 mg/kg 1 h after infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the SNpc. First, we assessed the motor behavior in the open field for 24 h, 7, 14 and 21 days after MPTP. Twenty-two days after surgery, the animals were tested for two-way active avoidance and forced swimming for evaluation regarding cognitive and depressive parameters, resp. Twenty-three days after infusion of the toxin, we quantified DA and turnover and evaluated oxidative stress through the measurement of GSH (glutathione peroxidase), SOD (superoxide dismutase) and LOOH (hydroperoxide lipid). The data show that fenofibrate was able to decrease hypolocomotion caused by MPTP 24 h after injury, depressive-like behavior 22 days after the toxin infusion, and also protected against decreased level of DA and excessive prodn. of reactive oxygen species (ROS) 23 days after surgery. Thus, fenofibrate has shown a neuroprotective effect in the MPTP model of Parkinson's disease.
- 72Martin, H. L.; Mounsey, R. B.; Sathe, K.; Mustafa, S.; Nelson, M. C.; Evans, R. M.; Teismann, P. A Peroxisome Proliferator-Activated Receptor-δ Agonist Provides Neuroprotection in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson’s Disease. Neuroscience 2013, 240, 191– 203, DOI: 10.1016/j.neuroscience.2013.02.058[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmsVGhs7s%253D&md5=f386ef071f15887b3027029ed80f9064A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's diseaseMartin, H. L.; Mounsey, R. B.; Sathe, K.; Mustafa, S.; Nelson, M. C.; Evans, R. M.; Teismann, P.Neuroscience (Amsterdam, Netherlands) (2013), 240 (), 191-203CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)Peroxisome proliferator-activated receptor (PPAR)-γ and PPARα have shown neuroprotective effects in models of Parkinson's disease (PD). The role of the third, more ubiquitous isoform PPARδ has not been fully explored. This study investigated the role of PPARδ in PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model the dopaminergic neurodegeneration of PD. In vitro administration of the PPARδ antagonist GSK0660 (1 μM) increased the detrimental effect of 1-methyl-4-phenylpyridinium iodide (MPP+) on cell viability, which was reversed by co-treatment with agonist GW0742 (1 μM). GW0742 alone did not affect MPP+ toxicity. PPARδ was expressed in the nucleus of dopaminergic neurons and in astrocytes. Striatal PPARδ levels were increased (over two-fold) immediately after MPTP treatment (30 mg/kg for 5 consecutive days) compared to saline-treated mice. PPARδ heterozygous mice were not protected against MPTP toxicity. Intra-striatal infusion of GW0742 (84 μg/day) reduced the MPTP-induced loss of dopaminergic neurons (5036 ± 195) when compared to vehicle-infused mice (3953 ± 460). These results indicate that agonism of PPARδ provides protection against MPTP toxicity, in agreement with the effects of other PPAR agonists.
- 73Lee, Y.; Cho, J.-H.; Lee, S.; Lee, W.; Chang, S.-C.; Chung, H. Y.; Moon, H. R.; Lee, J. Neuroprotective Effects of MHY908, a PPAR α/γ Dual Agonist, in a MPTP-Induced Parkinson’s Disease Model. Brain Res. 2019, 1704, 47– 58, DOI: 10.1016/j.brainres.2018.09.036[Crossref], [PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVGjur%252FE&md5=f81c90f7af067f46495c90315e3f22daNeuroprotective effects of MHY908, a PPAR a/g dual agonist, in a MPTP-induced Parkinson's disease modelLee, Yujeong; Cho, Jung-Hyun; Lee, Seulah; Lee, Wonjong; Chang, Seung-Cheol; Chung, Hae Young; Moon, Hyung Ryong; Lee, JaewonBrain Research (2019), 1704 (), 47-58CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)Here, we evaluated the neuroprotective effects of MHY908 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Pretreatment with MHY908 attenuated MPTP-induced dopaminergic neuronal loss and motor deficit. MPTP-induced glial activations were mitigated by MHY908 in the nigrostriatal pathway, and MHY908 effectively blocked 1-methyl-4-phenylpyridinium (MPP+)-induced cell death and ROS prodn. in SH-SY5Y neuroblastoma cells. Further study revealed MHY908 inhibited MPP+-induced astroglial activation by suppressing NF-kB signaling in primary astrocytes. Taken together, the present study suggests that PPAR a/dual agonists be considered potentially useful preventions for PD and other neurodegenerative diseases assocd. with neuroinflammation.
- 74Chen, L.; Xue, L.; Zheng, J.; Tian, X.; Zhang, Y.; Tong, Q. PPARß/δ Agonist Alleviates NLRP3 Inflammasome-Mediated Neuroinflammation in the MPTP Mouse Model of Parkinson’s Disease. Behav. Brain Res. 2019, 356, 483– 489, DOI: 10.1016/j.bbr.2018.06.005[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1agsb7I&md5=3c8e84371c2968069bfda5ade2238d17Pparss/δ agonist alleviates nlrp3 inflammasome-mediated neuroinflammation in the mptp mouse model of parkinson's diseaseChen, Linfang; Xue, Liujun; Zheng, Jinlong; Tian, Xiangyang; Zhang, Yingdong; Tong, QiangBehavioural Brain Research (2019), 356 (), 483-489CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)Recent studies have indicated that peroxisome proliferator-activated receptor β/δ (PPARss/δ) agonists exert neuroprotective effects in the model of Parkinson's disease (PD). Furthermore, PPARss/δ agonists have been shown to have potential anti-inflammatory activity, but the underlying mechanisms remain obscure. Emerging evidence indicates that the nucleotide-binding domain and leucine-rich-repeat-protein 3 (NLRP3) inflammasome-mediated neuroinflammation plays a crucial role in the pathogenesis of PD. In the present study we investigate whether PPARss/δ agonists alleviate NLRP3-mediated neuroinflammation in the 1- methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model of PD. We administered GW501516, a selective and high-affinity PPARss/δ agonist, via intracerebroventricular infusion. Locomotor activities were tested by open field tests and the pole test. The levels of dopamine and its metabolites were detd. using highperformance liq. chromatog. Dopaminergic neurodegeneration was assessed via Western blot anal. The levels of oxidative stress were detected via spectrophotometric assays. The expressions of pro-inflammatory cytokines were measured by performing quant. real-time RT-PCR and ELISA. Western blot anal. was used to assess NLRP3 inflammasome activation. Our results show that GW501516 reduced movement impairment in PD mice; furthermore, it attenuated dopaminergic neurodegeneration in the midbrain and the depletion of dopamine in the striatum and it inhibited inflammatory reactions and NLRP3 inflammasome activation in the midbrain of PD mice. More importantly, it attenuated astrocytic reaction but had no significant effect on microglial reaction in the midbrain of PD mice. Collectively, our findings demonstrate for the first time that the specific PPARss/δ agonist GW501516 alleviates NLRP3 inflammasome-mediated neuroinflammation in astrocytes in the MPTP mouse model of PD.
- 75Mounsey, R. B.; Martin, H. L.; Nelson, M. C.; Evans, R. M.; Teismann, P. The Effect of Neuronal Conditional Knock-out of Peroxisome Proliferator-Activated Receptors in the MPTP Mouse Model of Parkinson’s Disease. Neuroscience 2015, 300, 576– 584, DOI: 10.1016/j.neuroscience.2015.05.048[Crossref], [PubMed], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpsVymt7w%253D&md5=b88a0c77bcb54c7c09030ac571547439The effect of neuronal conditional knock-out of peroxisome proliferator-activated receptors in the MPTP mouse model of Parkinson's diseaseMounsey, R. B.; Martin, H. L.; Nelson, M. C.; Evans, R. M.; Teismann, P.Neuroscience (Amsterdam, Netherlands) (2015), 300 (), 576-584CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)Activation of peroxisome proliferator-activated receptors (PPARs), namely PPARγ and PPARδ, has been shown to provide neuroprotection in a no. of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease (PD). The obsd. neuroprotective effects in exptl. models of PD have been linked to anti-oxidant and anti-inflammatory actions. This study aimed to analyze the full influence of these receptors in neuroprotection by generating a nerve cell-specific conditional knock-out of these receptors and subjecting these genetically modified mice to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to model dopaminergic degeneration. Mice null for both receptors show the lowest levels of tyrosine hydroxylase (TH)-pos. cell bodies following MPTP administration. Presence of one or both these receptors show a trend toward protection against this degeneration, as higher dopaminergic cell immunoreactivity and striatal monoamine levels are evident. These data supplement recent studies that have elected to use agonists of the receptors to regulate immune responses. The results place further importance on the activation of PPARs and the neuroprotective roles these have in inflammatory processes linked to neurodegenerative processes.
- 76Tong, Q.; Wu, L.; Gao, Q.; Ou, Z.; Zhu, D.; Zhang, Y. PPARβ/δ Agonist Provides Neuroprotection by Suppression of IRE1α–Caspase-12-Mediated Endoplasmic Reticulum Stress Pathway in the Rotenone Rat Model of Parkinson’s Disease. Mol. Neurobiol. 2016, 53 (8), 3822– 3831, DOI: 10.1007/s12035-015-9309-9[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFKhu73F&md5=e3b59fa369bf8392cf8c7c8183f91d60PPARβ/δ Agonist Provides Neuroprotection by Suppression of IRE1α-Caspase-12-Mediated Endoplasmic Reticulum Stress Pathway in the Rotenone Rat Model of Parkinson's DiseaseTong, Qiang; Wu, Liang; Gao, Qing; Ou, Zhou; Zhu, Dongya; Zhang, YingdongMolecular Neurobiology (2016), 53 (6), 3822-3831CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Two recent studies demonstrated that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) agonists exerted neuroprotective effects in mouse model of Parkinson's disease (PD). However, the underlying mechanisms remain unknown. Endoplasmic reticulum (ER) stress plays a major role in rotenone-induced dopaminergic neuronal degeneration. In the present study, we explored whether GW501516, a selective and high-affinity PPARβ/δ agonist, could protect the dopaminergic neurons against degeneration and improve PD behavior via suppressing the ER stress in the rotenone rat model of PD. GW501516 was administered intracerebroventricular infusion. Catalepsy and open field tests were used to test catalepsy and locomotor activities. The levels of dopamine and its metabolites were detd. using high-performance liq. chromatog. Western blot and immunohistochem. anal. were performed to assess dopaminergic neuronal degeneration. Quant. real-time RT-PCR and Western blot anal. were executed to detect ER stress. TUNEL and immunohistochem. assays were used to detect ER stress-mediated apoptosis. Our results showed that GW501516 ameliorated the catalepsy symptom and increased locomotor activity. Meanwhile, GW501516 partially reversed the loss of dopaminergic neurons. Moreover, GW501516 suppressed the activation of ER stress markers including inositol-requiring enzyme 1α (IRE1α) and caspase-12. Furthermore, GW501516 inhibited caspase-12-mediated neuronal apoptosis. These findings suggest that GW501516 conferred neuroprotection of not only biochem. and pathol. attenuation but also behavioral improvement in the rotenone rat model of PD. More importantly, we demonstrated for the first time that suppressing IRE1α-caspase-12-mediated ER stress pathway may represent one potential mechanism underlying the neuroprotective effects of PPARβ/δ agonist in the rotenone rat model of PD.
- 77Bonato, J. M.; Bassani, T. B.; Milani, H.; Vital, M. A. B. F.; de Oliveira, R. M. W. Pioglitazone Reduces Mortality, Prevents Depressive-like Behavior, and Impacts Hippocampal Neurogenesis in the 6-OHDA Model of Parkinson’s Disease in Rats. Exp. Neurol. 2018, 300, 188– 200, DOI: 10.1016/j.expneurol.2017.11.009[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFaqu7%252FJ&md5=b0e6773d9e5aec41f39ffb95e03385faPioglitazone reduces mortality, prevents depressive-like behavior, and impacts hippocampal neurogenesis in the 6-OHDA model of Parkinson's disease in ratsBonato, Jessica Mendes; Bassani, Taysa Bervian; Milani, Humberto; Vital, Maria Aparecida Barbato Frazao; de Oliveira, Rubia Maria WeffortExperimental Neurology (2018), 300 (), 188-200CODEN: EXNEAC; ISSN:0014-4886. (Elsevier Inc.)Deficiencies in adult hippocampal neurogenesis have been suggested to be a possible pathophysiol. mechanism that underlies depressive symptoms that are often obsd. in patients with Parkinson's disease (PD). Pioglitazone, a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, has been shown to exert antiinflammatory and antidepressant effects and modulate neural plasticity in several neurodegenerative disorders. The present study investigated the effects of pioglitazone on depressive phenotypes and adult hippocampal neurogenesis in a rat model of PD that was induced by bilateral 6-hydroxydopamine (6-OHDA) infusions in the substantia nigra pars compact (SNpc). Rats with SNpc and ventral tegmental area (VTA) neurodegeneration exhibited despair-like behavior, concomitant with persistent microglial activation in the hippocampus. Pioglitazone reduced the rate of mortality and attenuated microglial activation in the early phase of 6-OHDA-induced nigral lesions. Pioglitazone exerted antidepressant-like effects and increased the survival of neurons in the hippocampus in rats with nigral lesions. These results indicate that pioglitazone exerts neuroprotective effects by facilitating hippocampal neurogenesis in 6-OHDA-lesioned rats, which might contribute to its antidepressant-like effect.
- 78Machado, M. M. F.; Bassani, T. B.; Cóppola-Segovia, V.; Moura, E. L. R.; Zanata, S. M.; Andreatini, R.; Vital, M. A. B. F. PPAR-γ Agonist Pioglitazone Reduces Microglial Proliferation and NF-KB Activation in the Substantia Nigra in the 6-Hydroxydopamine Model of Parkinson’s Disease. Pharmacol. Rep. 2019, 71 (4), 556– 564, DOI: 10.1016/j.pharep.2018.11.005[Crossref], [PubMed], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVegu7zJ&md5=393a932f3b2e0814357c21c4153d7c02PPAR-γ agonist pioglitazone reduces microglial proliferation and NF-κB activation in the substantia nigra in the 6-hydroxydopamine model of Parkinson's diseaseMachado, Meira Maria Forcelini; Bassani, Taysa Bervian; Coppola-Segovia, Valentin; Moura, Eric Luiz Rossa; Zanata, Silvio Marques; Andreatini, Roberto; Vital, Maria Aparecida Barbato FrazaoPharmacological Reports (2019), 71 (4), 556-564CODEN: PRHEDU; ISSN:2299-5684. (Elsevier B.V.)Peroxisome proliferator-activated receptor γ (PPAR-γ) agonists have received much attention in research because of their neuroprotective and anti-inflammatory effects that reduce cell death and halt the progression of neurodegeneration. Thus, this study obsd. the pioglitazone effects on the main inflammatory markers after 6-hydroxydopamine (6-OHDA) lesion. The effects of a 5-day administration of the PPAR-γ agonist pioglitazone (30 mg/kg) in male Wistar rats that received bilateral intranigral infusions of 6-OHDA. After surgery, the rats were evaluated in the open-field test on days 1,7,14, and 21. Immediately after the behavioral tests on day 21, the rats were euthanized, and the substantia nigra was removed to analyze the expression of nuclear factor κB (NF-κB) and IκB by western blot. To immunohistochem., animals were intracardially perfused, with brain removal that was frozen and sectioned, being selected slices of the SNc region to detect tyrosine hydroxylase (TH) immunoreactivity, microglia activation (Iba-1) and NF-κB translocation in the nucleus. Pioglitazone protected rats against hypolocomotion and 6-OHDA-induced dopaminergic neurodegeneration on day 7. Decreases in the microglial activation and the NF-κB expression were obsd., and the p65 activation was inhibited. These results suggest that pioglitazone may be a potential adjuvant for the treatment of Parkinson's disease because of its effects on pathol. markers of the progression of neurodegeneration.
- 79Lee, E. Y.; Lee, J. E.; Park, J. H.; Shin, I. C.; Koh, H. C. Rosiglitazone, a PPAR-γ Agonist, Protects against Striatal Dopaminergic Neurodegeneration Induced by 6-OHDA Lesions in the Substantia Nigra of Rats. Toxicol. Lett. 2012, 213 (3), 332– 344, DOI: 10.1016/j.toxlet.2012.07.016[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlSnsL%252FE&md5=add46159419011ab9bef26dc89de04adRosiglitazone, a PPAR-γ agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of ratsLee, Eun Young; Lee, Jeong Eun; Park, Jae Hyeon; Shin, In Chul; Koh, Hyun ChulToxicology Letters (2012), 213 (3), 332-344CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Rosiglitazone is a commonly prescribed insulin-sensitizing drug with selective agonistic activity at the peroxisome proliferator-activated receptor-γ (PPARγ). Previously, rosiglitazone was shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), an effect attributed to its anti-inflammatory properties. To elucidate the neuroprotective mechanisms of rosiglitazone, we investigated the effects of rosiglitazone on the expressions of striatal tyrosine hydroxylase (TH), cyclooxygenase-2 (COX-2) and glial fibrillary acidic protein (GFAP) in a 6-OHDA-lesioned rat PD model. Rosiglitazone (3 mg/kg) was administered i.p. at 24 h and 30 min prior to the creation of an intranigral 6-OHDA lesion. A redn. in TH protein expression began at 3 days and a prominent decrease was obsd. at 7 days post-lesion, and decreases of dopamine (DA) levels began at 1 day post-lesion. In contrast, GFAP expression was significantly increased at 3 days and preserved for up to 7 days post-lesion and the patterns of GFAP expression was inversely correlated to changes in TH expression. Furthermore, COX-2 expression in the rostral striatum showed a significant increase at 6 h post-lesion while that of the caudal striatum was increased at 12 h. In the 6-OHDA-lesioned model, the activation of PPARγ by rosiglitazone significantly prevented TH protein expression redns., and inhibited 6-OHDA-induced microglia activation in striatum. In addn., rosiglitazone attenuated in prodn. of both COX-2 and TNF-α expression. In contrast, rosiglitazone pretreatment led to greater increases in striatal GFAP expression than 6-OHDA alone and changes in the expression of this protein preceded the changes that were seen with TH expression. These results suggest that the neuroprotection obsd. with rosiglitazone treatment may be partially due to the attenuation of COX-2 prodn. and the strengthening of astrocyte function. These results provide insight into the neuroprotective mechanisms of rosiglitazone against 6-OHDA-induced neuronal damages.
- 80Martinez, A. A.; Morgese, M. G.; Pisanu, A.; Macheda, T.; Paquette, M. A.; Seillier, A.; Cassano, T.; Carta, A. R.; Giuffrida, A. Activation of PPAR Gamma Receptors Reduces Levodopa-Induced Dyskinesias in 6-OHDA-Lesioned Rats. Neurobiol. Dis. 2015, 74, 295– 304, DOI: 10.1016/j.nbd.2014.11.024[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitV2msL%252FF&md5=c91b97782ba953b7623a89c77b0493d6Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned ratsMartinez, A. A.; Morgese, M. G.; Pisanu, A.; Macheda, T.; Paquette, M. A.; Seillier, A.; Cassano, T.; Carta, A. R.; Giuffrida, A.Neurobiology of Disease (2015), 74 (), 295-304CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)Long-term administration of L-3,4-dihydroxyphenylalanine (levodopa), the mainstay treatment for Parkinson's disease (PD), is accompanied by fluctuations in its duration of action and motor complications (dyskinesia) that dramatically affect the quality of life of patients. Levodopa-induced dyskinesias (LID) can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of levodopa, which causes increasingly severe axial, limb, and orofacial abnormal involuntary movements (AIMs) over time. In previous studies, we showed that the direct activation of CB1 cannabinoid receptors alleviated rat AIMs. Interestingly, elevation of the endocannabinoid anandamide by URB597 (URB), an inhibitor of endocannabinoid catabolism, produced an anti-dyskinetic response that was only partially mediated via CB1 receptors and required the concomitant blockade of transient receptor potential vanilloid type-1 (TRPV1) channels by capsazepine (CPZ) (Morgese et al., 2007). In this study, we showed that the stimulation of peroxisome proliferator-activated receptors (PPAR), a family of transcription factors activated by anandamide, contributes to the anti-dyskinetic effects of URB + CPZ, and that the direct activation of the PPARγ subtype by rosiglitazone (RGZ) alleviates levodopa-induced AIMs in 6-OHDA rats. AIM redn. was assocd. with an attenuation of levodopa-induced increase of dynorphin, zif-268, and of ERK phosphorylation in the denervated striatum. RGZ treatment did not decrease striatal levodopa and dopamine bioavailability, nor did it affect levodopa anti-parkinsonian activity. Collectively, these data indicate that PPARγ may represent a new pharmacol. target for the treatment of LID.
- 81Gottschalk, C. G.; Roy, A.; Jana, M.; Kundu, M.; Pahan, K. Activation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic Neurons. Mol. Neurobiol. 2019, 56 (11), 7872– 7887, DOI: 10.1007/s12035-019-01649-y[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVCitLrO&md5=1e18d8ef00f254fdefa0e10784ffa4faActivation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic NeuronsGottschalk, Carl G.; Roy, Avik; Jana, Malabendu; Kundu, Madhuchhanda; Pahan, KalipadaMolecular Neurobiology (2019), 56 (11), 7872-7887CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Nuclear receptor related 1 protein (Nurr1) is an important transcription factor required for differentiation and maintenance of midbrain dopaminergic (DA) neurons. Since decrease in Nurr1 function either due to diminished expression or rare mutation is assocd. with Parkinson's disease (PD), upregulation of Nurr1 may be beneficial for PD. However, such mechanisms are poorly understood. This study underlines the importance of peroxisome proliferator-activated receptor (PPAR)α in controlling the transcription of Nurr1. Our mRNA analyses followed by different immunoassays clearly indicated that PPARα agonist gemfibrozil strongly upregulated the expression of Nurr1 in wild-type, but not PPARα-/-, DA neurons. Moreover, identification of conserved PPRE in the promoter of Nurr1 gene followed by chromatin immunopptn. anal., PPRE luciferase assay, and manipulation of Nurr1 gene by viral transduction of different PPARα plasmids confirmed that PPARα was indeed involved in the expression of Nurr1. Finally, oral administration of gemfibrozil increased Nurr1 expression in vivo in nigra of wild-type, but not PPARα-/-, mice identifying PPARα as a novel regulator of Nurr1 expression and assocd. protection of DA neurons.
- 82Brauer, R.; Bhaskaran, K.; Chaturvedi, N.; Dexter, D. T.; Smeeth, L.; Douglas, I. Glitazone Treatment and Incidence of Parkinson’s Disease among People with Diabetes: A Retrospective Cohort Study. PLoS Med. 2015, 12 (7), e1001854, DOI: 10.1371/journal.pmed.1001854[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlsFOgu7k%253D&md5=b5a6318677eb4d902ccf391705669b5eGlitazone treatment and incidence of parkinson's disease among people with diabetes: a retrospective cohort studyBrauer, Ruth; Bhaskaran, Krishnan; Chaturvedi, Nishi; Dexter, David T.; Smeeth, Liam; Douglas, IanPLoS Medicine (2015), 12 (7), e1001854/1-e1001854/16CODEN: PMLEAC; ISSN:1549-1277. (Public Library of Science)Background Recent in vitro and animal expts. suggest that peroxisome proliferation-activated receptor gamma (PPARγ) agonist medications, such as antidiabetic glitazone (GTZ) drugs, are neuroprotective in models of Parkinson's disease (PD). These findings have not been tested in humans. We hypothesized that individuals prescribed GTZ drugs would have a lower incidence of PD compared to individuals prescribed other treatments for diabetes. Methods and Findings Using primary care data from the United Kingdom Clin. Practice Research Datalink (CPRD), we conducted a retrospective cohort study in which individuals with diabetes who were newly prescribed GTZ (GTZ-exposed group) were matched by age, sex, practice, and diabetes treatment stage with up to five individuals prescribed other diabetes treatments (other antidiabetic drug-exposed group). Patients were followed up from 1999 until the first recording of a PD diagnosis, end of observation in the database, or end of the study (1 August 2013). An incidence rate ratio (IRR) was calcd. using conditional Poisson regression, adjusted for possible confounders. 44,597 GTZ exposed individuals were matched to 120,373 other antidiabetic users. 175 GTZ-exposed individuals were diagnosed with PD compared to 517 individuals in the other antidiabetic drug-exposed group. The incidence rate (IR) of PD in the GTZ-exposed group was 6.4 per 10,000 patient years compared with 8.8 per 10,000 patient years in those prescribed other antidiabetic treatments (IRR 0.72, 95% confidence interval [CI] 0.60-0.87). Adjustments for potential confounding variables, including smoking, other medications, head injury, and disease severity, had no material impact (fully adjusted IRR 0.75, 0.59-0.94). The risk was reduced in those with current GTZ prescriptions (current GTZ-exposed IRR 0.59, 0.46-0.77) but not reduced among those with past prescriptions (past GTZ-exposed IRR 0.85, 0.65-1.10). Our study only included patients with diabetes who did not have a PD diagnosis when they were first prescribed GTZ, and thus, it cannot establish whether GTZ use prevents or slows the progression of PD. Conclusions In patients with diabetes, a current prescription for GTZ is assocd. with a redn. in incidence of PD. This suggests PPAR gamma pathways may be a fruitful drug target in PD.
- 83Mutez, E.; Duhamel, A.; Defebvre, L.; Bordet, R.; Destée, A.; Kreisler, A. Lipid-Lowering Drugs Are Associated with Delayed Onset and Slower Course of Parkinson’s Disease. Pharmacol. Res. 2009, 60 (1), 41– 45, DOI: 10.1016/j.phrs.2009.03.010[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlslWlu7w%253D&md5=8b0c8dcff57b176f8b2a76a5981cf4cfLipid-lowering drugs are associated with delayed onset and slower course of Parkinson's diseaseMutez, Eugenie; Duhamel, Alain; Defebvre, Luc; Bordet, Regis; Destee, Alain; Kreisler, AlexandrePharmacological Research (2009), 60 (1), 41-45CODEN: PHMREP; ISSN:1043-6618. (Elsevier Ltd.)Fibrates and statins activate the Peroxisome Proliferator-Activated Receptor alpha (PPAR-alpha). This nuclear receptor regulates genes governing inflammation, apoptosis and oxidative stress, three important mechanisms of neuronal death in Parkinson's disease (PD). We retrospectively studied the effect of statins and fibrates in a cohort of 419 patients with PD. In PD patients receiving either a statin or a fibrate, the mean age of disease onset was delayed by nearly 9 years, when compared with (control) PD patients not taking a lipid-lowering treatment. According to a mixed linear model, the increase in the levodopa-equiv. daily dose over 2 years was significantly smaller in the group taking a statin (+24 mg) than in the matched control group (+212 mg) (p = 0.004), whereas the Unified Parkinson's Disease Rating Scale motor score progression was similar. The course of the disease in patients taking a fibrate did not differ from the controls. These data suggest that lipid-lowering drugs may have a disease modifier effect, with a stronger action for statins than for fibrates.
- 84Szalardy, L.; Zadori, D.; Tanczos, E.; Simu, M.; Bencsik, K.; Vecsei, L.; Klivenyi, P. Elevated Levels of PPAR-Gamma in the Cerebrospinal Fluid of Patients with Multiple Sclerosis. Neurosci. Lett. 2013, 554, 131– 134, DOI: 10.1016/j.neulet.2013.08.069[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslCls7zN&md5=ca0cdef78d24e6b93a0a4e15a312ae82Elevated levels of PPAR-gamma in the cerebrospinal fluid of patients with multiple sclerosisSzalardy, Levente; Zadori, Denes; Tanczos, Ervin; Simu, Mihaela; Bencsik, Krisztina; Vecsei, Laszlo; Klivenyi, PeterNeuroscience Letters (2013), 554 (), 131-134CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcriptional factor involved in the regulation of glucose and lipid metab., has gained interest as a potential therapeutic target in multiple sclerosis (MS) due to its potent immunoregulatory properties and the therapeutic efficacy of its ligands in exptl. autoimmune encephalitis (EAE). Elevated expression of PPARγ has been obsd. in the spinal cord of EAE mice and in an in vitro model of antigen-induced demyelination; however, no reports have yet been available on the PPARγ status in the central nervous system of human individuals with MS. Aiming to identify a possible alteration, the present study assessed the levels of PPARγ protein in the cerebrospinal fluid (CSF) of MS patients via ELISA technique. We report a pronounced elevation in the CSF levels of PPARγ in MS patients (n = 35) compared to non-inflammatory controls (n = 22). This elevation was independent of blood-CSF barrier integrity, but correlated with CSF white blood cell count and IgG index, assocg. the obsd. elevation with neuroinflammation. Controlling for potential confounders, the CSF levels of PPARγ further displayed a moderate but significant assocn. with clin. severity. Corroborating with prior exptl. findings, these results may contribute to our understanding about the role of PPARγ in MS, and may implicate this protein as a potential CSF biomarker of the disease.
- 85Szalardy, L.; Zadori, D.; Bencsik, K.; Vecsei, L.; Klivenyi, P. Unlike PPARgamma, Neither Other PPARs nor PGC-1alpha Is Elevated in the Cerebrospinal Fluid of Patients with Multiple Sclerosis. Neurosci. Lett. 2017, 651, 128– 133, DOI: 10.1016/j.neulet.2017.05.008[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXns1als7k%253D&md5=e145306ea529f1a35e307f9c794eea34Unlike PPARgamma, neither other PPARs nor PGC-1alpha is elevated in the cerebrospinal fluid of patients with multiple sclerosisSzalardy, Levente; Zadori, Denes; Bencsik, Krisztina; Vecsei, Laszlo; Klivenyi, PeterNeuroscience Letters (2017), 651 (), 128-133CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Corroborating with prior exptl. findings, we recently reported the pronounced elevation of peroxisome proliferator-activated receptor gamma (PPARγ) protein concn. in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS), in assocn. with neuroinflammatory markers and clin. severity. Based on subsequent reports on the possible involvement of other PPARs and PPARγ coactivator-1alpha (PGC-1α) in neuroinflammation in MS, we analyzed the protein levels of PPARα, PPARβ/δ, and PGC-1α in a subset of CSF samples from the same cohort of relapsing-remitting MS patients. Unlike PPARγ, none of these proteins were found elevated in MS patients (n = 25) compared to non-inflammatory controls (n = 16), with the levels of PPARα and PPARβ/δ found generally below the limit of detection, and that of PGC-1α being detectable but comparable in both groups. The clin. and lab. assocns. previously reported with PPARγ were however significant even in this smaller subset. The potential underlying causes of these differential alterations are discussed. The findings suggest that despite their proposed involvement in the regulation of inflammatory processes in MS, PPARα, PPARβ/δ, and PGC-1α proteins are not potential biomarkers of neuroinflammation in MS, and indicate a preferential role of PPARγ in the endogenous regulation of autoimmune response in the human CNS within its receptor family.
- 86Wouters, E.; Grajchen, E.; Jorissen, W.; Dierckx, T.; Wetzels, S.; Loix, M.; Tulleners, M. P.; Staels, B.; Stinissen, P.; Haidar, M.; Bogie, J. F. J.; Hendriks, J. J. A. Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis. Int. J. Mol. Sci. 2020, 21 (23), 9329, DOI: 10.3390/ijms21239329[Crossref], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXotVyitA%253D%253D&md5=3b492c9f1e5a0cc035226e3d12ff9e1dAltered PPARγ expression promotes myelin-induced foam cell formation in macrophages in multiple sclerosisWouters, Elien; Grajchen, Elien; Jorissen, Winde; Dierckx, Tess; Wetzels, Suzan; Loix, Melanie; Tulleners, Marie Paule; Staels, Bart; Stinissen, Piet; Haidar, Mansour; Bogie, Jeroen F. J.; Hendriks, Jerome J. A.International Journal of Molecular Sciences (2020), 21 (23), 9329CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)Macrophages play a crucial role during the pathogenesis of multiple sclerosis (MS), a neuroinflammatory autoimmune disorder of the central nervous system. Important regulators of the metabolic and inflammatory phenotype of macrophages are liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). Previously, it has been reported that PPARγ expression is decreased in peripheral blood mononuclear cells of MS patients. The goal of the present study was to det. to what extent PPARγ, as well as the closely related nuclear receptors PPARα and β and LXRα and β, are differentially expressed in monocytes from MS patients and how this change in expression affects the function of monocyte-derived macrophages. We demonstrate that monocytes of relapsing-remitting MS patients display a marked decrease in PPARγ expression, while the expression of PPARα and LXRα/β is not altered. Interestingly, exposure of monocyte-derived macrophages from healthy donors to MS-assocd. proinflammatory cytokines mimicked this redn. in PPARγ expression. While a reduced PPARγ expression did not affect the inflammatory and phagocytic properties of myelin-loaded macrophages, it did impact myelin processing by increasing the intracellular cholesterol load of myelin-phagocytosing macrophages. Collectively, our findings indicate that an inflammation-induced redn. in PPARγ expression promotes myelin-induced foam cell formation in macrophages in MS.
- 87Feinstein, D. L.; Galea, E.; Gavrilyuk, V.; Brosnan, C. F.; Whitacre, C. C.; Dumitrescu-Ozimek, L.; Landreth, G. E.; Pershadsingh, H. A.; Weinberg, G.; Heneka, M. T. Peroxisome Proliferator-Activated Receptor-γ Agonists Prevent Experimental Autoimmune Encephalomyelitis. Ann. Neurol. 2002, 51 (6), 694– 702, DOI: 10.1002/ana.10206[Crossref], [PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhsFygsb0%253D&md5=8c9aad931d21860ef88dd3d987d66dcdPeroxisome proliferator-activated receptor-γ agonists prevent experimental autoimmune encephalomyelitisFeinstein, Douglas L.; Galea, Elena; Gavrilyuk, Vitaliy; Brosnan, Celia F.; Whitacre, Caroline C.; Dumitrescu-Ozimek, Lucia; Landreth, Gary E.; Pershadsingh, Harrihar A.; Weinberg, Guy; Heneka, Michael T.Annals of Neurology (2002), 51 (6), 694-702CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)The development of clin. symptoms in multiple sclerosis and its animal model exptl. autoimmune encephalomyelitis (EAE) involves T-cell activation and migration into the central nervous system, prodn. of glial-derived inflammatory mols., and demyelination and axonal damage. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARγ ligand Pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clin. signs when it was provided after disease onset. Clin. symptoms were reduced by two other PPARγ agonists, suggesting a role for PPARγ activation in protective effects. The suppression of clin. signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen-dependent interferon-γ prodn. from EAE-derived T cells. These results suggest that orally administered PPARγ agonists could provide therapeutic benefit in demyelinating disease.
- 88Klotz, L.; Burgdorf, S.; Dani, I.; Saijo, K.; Flossdorf, J.; Hucke, S.; Alferink, J.; Novak, N.; Beyer, M.; Mayer, G.; Langhans, B.; Klockgether, T.; Waisman, A.; Eberl, G.; Schultze, J.; Famulok, M.; Kolanus, W.; Glass, C.; Kurts, C.; Knolle, P. The Nuclear Receptor PPARγ Selectively Inhibits Th17 Differentiation in a T Cell–Intrinsic Fashion and Suppresses CNS Autoimmunity. J. Exp. Med. 2009, 206 (10), 2079– 2089, DOI: 10.1084/jem.20082771[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1SrtbvE&md5=a0d5f5c62100d9c29abbc84d8f3f9216The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunityKlotz, Luisa; Burgdorf, Sven; Dani, Indra; Saijo, Kaoru; Flossdorf, Juliane; Hucke, Stephanie; Alferink, Judith; Novak, Nina; Beyer, Marc; Mayer, Gunter; Langhans, Birgit; Klockgether, Thomas; Waisman, Ari; Eberl, Gerard; Schultze, Joachim; Famulok, Michael; Kolanus, Waldemar; Glass, Christopher; Kurts, Christian; Knolle, Percy A.Journal of Experimental Medicine (2009), 206 (10), 2079-2089CODEN: JEMEAV; ISSN:0022-1007. (Rockefeller University Press)T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-β/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor-related orphan receptor γt (RORγt). We identify the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) as a key neg. regulator of human and mouse Th17 differentiation. PPARγ activation in CD4+ T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPARγ involved inhibition of TGF-β/IL-6-induced expression of RORγt in T cells. Pharmacol. activation of PPARγ prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the RORγt promoter in T cells, thus interfering with RORγt transcription. Both T cell-specific PPARγ knockout and endogenous ligand activation revealed the physiol. role of PPARγ for continuous T cell-intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4+ T cells from healthy controls and MS patients were strongly susceptible to PPARγ-mediated suppression of Th17 differentiation. In summary, we report a PPARγ-mediated T cell-intrinsic mol. mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacol. modulation. We therefore propose that PPARγ represents a promising mol. target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.
- 89Chedrawe, M. A. J.; Holman, S. P.; Lamport, A.-C.; Akay, T.; Robertson, G. S. Pioglitazone Is Superior to Quetiapine, Clozapine and Tamoxifen at Alleviating Experimental Autoimmune Encephalomyelitis in Mice. J. Neuroimmunol. 2018, 321, 72– 82, DOI: 10.1016/j.jneuroim.2018.06.001[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFSqsL7M&md5=a684196848748f42945705de45477401Pioglitazone is superior to quetiapine, clozapine and tamoxifen at alleviating experimental autoimmune encephalomyelitis in miceChedrawe, Matthew A. J.; Holman, Scott P.; Lamport, Anna-Claire; Akay, Turgay; Robertson, George S.Journal of Neuroimmunology (2018), 321 (), 72-82CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)Recent evidence suggests that clozapine and quetiapine (atypical antipsychotics), tamoxifen (selective-estrogen receptor modulator) and pioglitazone (PPARγ agonist) may improve functional recovery in multiple sclerosis (MS). We have compared the effectiveness of oral administration of these drugs, beginning at peak disease, at reducing ascending paralysis, motor deficits and demyelination in mice subjected to exptl. autoimmune encephalomyelitis (EAE). Mice were immunized with an immunogenic peptide corresponding to amino acids 35-55 of the myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant and injected with pertussis toxin to induce EAE. Unlike clozapine, quetiapine and tamoxifen, administration of pioglitazone beginning at peak disease decreased both clin. scores and lumbar white matter loss in EAE mice. Using kinematic gait anal., we found that pioglitazone also maintained normal movement of the hip, knee and ankle joints for at least 44 days after MOG35-55 immunization. This long-lasting preservation of hindleg joint movements was accompanied by reduced white matter loss, microglial and macrophage activation and the expression of pro-inflammatory genes in the lumbar spinal cords of EAE mice. These results support clin. findings that suggest pioglitazone may reduce the progressive loss of motor function in MS by decreasing inflammation and myelin damage.
- 90Diab, A.; Deng, C.; Smith, J. D.; Hussain, R. Z.; Phanavanh, B.; Lovett-Racke, A. E.; Drew, P. D.; Racke, M. K. Peroxisome Proliferator-Activated Receptor-γ Agonist 15-Deoxy-Δ12,1412,14-Prostaglandin J2 Ameliorates Experimental Autoimmune Encephalomyelitis. J. Immunol. 2002, 168 (5), 2508– 2515, DOI: 10.4049/jimmunol.168.5.2508[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhvVegsbk%253D&md5=73e71568a1466397765d5400221c5bd2Peroxisome proliferator-activated receptor-γ agonist 15-deoxy-Δ12,14-prostaglandin J2 ameliorates experimental autoimmune encephalomyelitisDiab, Asim; Deng, Caishu; Smith, Jeff D.; Hussain, Rehana Z.; Phanavanh, Bounleut; Lovett-Racke, Amy E.; Drew, Paul D.; Racke, Michael K.Journal of Immunology (2002), 168 (5), 2508-2515CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)Peroxisome proliferator-activated receptors (PPAR) are members of a nuclear hormone receptor superfamily that includes receptors for steroids, retinoids, and thyroid hormone, all of which are known to affect the immune response. Previous studies dealing with PPAR-γ expression in the immune system have been limited. Recently, PPAR-γ was identified in monocyte/macrophages. Here, the authors examd. the role of PPAR-γ in exptl. autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. The hypothesis the authors are testing is whether PPAR-γ plays an important role in EAE pathogenesis and whether PPAR-γ ligands can inhibit the clin. expression of EAE. Initial studies have shown that the presence of the PPAR-γ ligand 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) inhibits the proliferation of Ag-specific T cells from the spleen of myelin basic protein Ac1-11 TCR-transgenic mice. 15D-PGJ2 suppressed IFN-γ, IL-10, and IL-4 prodn. by both Con A- and myelin basic protein Ac1-11 peptide-stimulated lymphocytes as detd. by ELISA and ELISPOT assay. Culture of encephalitogenic T cells with 15d-PGJ2 in the presence of Ag reduced the ability of these cells to adoptively transfer EAE. Examn. of the target organ, the CNS, during the course of EAE revealed expression of PPAR-γ in the spinal cord inflammatory infiltrate. Administration of 15d-PGJ2 before and at the onset of clin. signs of EAE reduced the severity of disease. Thus, PPAR-γ ligands may be a novel therapeutic agent for diseases such as multiple sclerosis.
- 91Diab, A.; Hussain, R. Z.; Lovett-Racke, A. E.; Chavis, J. A.; Drew, P. D.; Racke, M. K. Ligands for the Peroxisome Proliferator-Activated Receptor-γ and the Retinoid X Receptor Exert Additive Anti-Inflammatory Effects on Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 2004, 148 (1–2), 116– 126, DOI: 10.1016/j.jneuroim.2003.11.010[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXht1yksb8%253D&md5=8d1bd671a66d35d5786ee5fa5c5f6fecLigands for the peroxisome proliferator-activated receptor-γ and the retinoid X receptor exert additive anti-inflammatory effects on experimental autoimmune encephalomyelitisDiab, Asim; Hussain, Rehana Z.; Lovett-Racke, Amy E.; Chavis, Janet A.; Drew, Paul D.; Racke, Michael K.Journal of Neuroimmunology (2004), 148 (1-2), 116-126CODEN: JNRIDW; ISSN:0165-5728. (Elsevier Science B.V.)Peroxisome proliferator-activated receptor-gamma (PPAR-γ) is a member of the nuclear-receptor superfamily that binds to DNA with retinoid x receptors (RXRs) as PPAR-RXR heterodimers. In exptl. autoimmune encephalomyelitis (EAE), the gene expression of PPAR-γ was demonstrated in spinal cord during the course of EAE. Administration of 15-deoxy-12,14-prostaglandin J2 (15d-PGJ2) or 9-cis-retinoic acid (RA) alone at the onset of clin. signs of EAE reduced the severity of disease, however, their combination resulted in enhanced amelioration of disease. These results suggest that use of RXR specific ligands may be highly effective when combined with PPAR-γ agonists in the treatment of autoimmune demyelinating diseases such as multiple sclerosis (MS).
- 92Bernardo, A.; Giammarco, M. L.; De Nuccio, C.; Ajmone-Cat, M. A.; Visentin, S.; De Simone, R.; Minghetti, L. Docosahexaenoic Acid Promotes Oligodendrocyte Differentiation via PPAR-γ Signalling and Prevents Tumor Necrosis Factor-α-Dependent Maturational Arrest. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2017, 1862 (9), 1013– 1023, DOI: 10.1016/j.bbalip.2017.06.014[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFSit7vO&md5=0bf4ccaceef726be5cfa3d5f06731876Docosahexaenoic acid promotes oligodendrocyte differentiation via PPAR-γ signalling and prevents tumor necrosis factor-α-dependent maturational arrestBernardo, A.; Giammarco, M. L.; De Nuccio, C.; Ajmone-Cat, M. A.; Visentin, S.; De Simone, R.; Minghetti, L.Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2017), 1862 (9), 1013-1023CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B.V.)Docosahexaenoic acid (DHA) is an essential omega-3 fatty acid known to be neuroprotective in several models of human diseases, including multiple sclerosis. The protective effects of DHA are largely attributed to its ability to interfere with the activity of transcription factors controlling immune and inflammatory responses, including the agonist-dependent transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ). In this study, we used primary oligodendrocyte progenitor (OP) cultures from neonatal rat brain to investigate whether DHA could influence OP maturation and directly promote myelination, as previously reported for selective PPAR-γ agonists. We show that, similarly to the selective PPAR-γ agonist pioglitazone (PGZ), DHA promotes OP maturation and counteracts the maturational arrest induced by TNF-α, used to mimic inflammatory conditions. The PPAR-γ antagonist GW9662 prevented both DHA-induced OP maturation and PPAR-γ nuclear translocation, supporting the hypothesis that DHA acts through the activation of PPAR-γ. In addn., both PGZ and DHA induced the phosphorylation of extracellular signal-regulated-kinase 1-2 (ERK1/2), in a PPAR-γ-dependent manner. ERK1/2 activity is known to regulate the transition from OPs to immature oligodendrocytes and the presence of specific inhibitors of ERK1/2 phosphorylation (U0126 or PD98059) prevented the differentiating effects of both DHA and PGZ. These results indicate that DHA might influence the process of OP maturation through its PPAR-γ agonistic activity and provide novel mol. mechanisms for the action of this dietary fatty acid, further supporting the nutritional intervention in demyelinating diseases such as multiple sclerosis.
- 93De Nuccio, C.; Bernardo, A.; Cruciani, C.; De Simone, R.; Visentin, S.; Minghetti, L. Peroxisome Proliferator Activated Receptor-γ Agonists Protect Oligodendrocyte Progenitors against Tumor Necrosis Factor-Alpha-Induced Damage: Effects on Mitochondrial Functions and Differentiation. Exp. Neurol. 2015, 271, 506– 514, DOI: 10.1016/j.expneurol.2015.07.014[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Ogs7rL&md5=dd69f6647de2b9d99c16bfa43b53d050Peroxisome proliferator activated receptor-γ agonists protect oligodendrocyte progenitors against tumor necrosis factor-alpha-induced damage: Effects on mitochondrial functions and differentiationDe Nuccio, C.; Bernardo, A.; Cruciani, C.; De Simone, R.; Visentin, S.; Minghetti, L.Experimental Neurology (2015), 271 (), 506-514CODEN: EXNEAC; ISSN:0014-4886. (Elsevier Inc.)The activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is known to exert anti-inflammatory and neuroprotective effects and PPAR-γ agonists are considered potential therapeutic agents in brain diseases including those affecting myelin. In demyelinating diseases such as multiple sclerosis (MS), inflammation is one of the causes of myelin and axonal damage. Oligodendrocyte (OL) differentiation is highly dependent on mitochondria, which are major targets of inflammatory insult. Here we show that PPAR-γ agonists protect OL progenitors against the maturational arrest induced by the inflammatory cytokine TNF-α by affecting mitochondrial functions. We demonstrate that the inhibition of OL differentiation by TNF-α is assocd. with (i) increased mitochondrial superoxide prodn.; (ii) decreased mitochondrial membrane potential (mMP); and (iii) decreased ADP-induced Ca2 + oscillations, which we previously showed to be dependent on efficient mitochondria. The TNF-α effects were comparable to those of the mitochondrial toxin rotenone, further suggesting that TNF-α damage is mediated by mitochondrial function impairment. PPAR-γ agonists protected OL progenitors against the inhibitory activities of both TNF-α and rotenone on mMP, mitochondrial ROS prodn., Ca2+ oscillations and OL differentiation. Finally, the PPAR-γ agonist pioglitazone increased the expression of PGC-1α (a mitochondrial biogenesis master regulator), UCP2 (a mitochondrial protein known to reduce ROS prodn.), and cytochrome oxidase subunit COX1. These findings confirm the central role of mitochondria in OL differentiation and point to mitochondria as major targets of PPAR-γ agonist protection against TNF-α damage.
- 94Storer, P. D.; Xu, J.; Chavis, J.; Drew, P. D. Peroxisome Proliferator-Activated Receptor-Gamma Agonists Inhibit the Activation of Microglia and Astrocytes: Implications for Multiple Sclerosis. J. Neuroimmunol. 2005, 161 (1–2), 113– 122, DOI: 10.1016/j.jneuroim.2004.12.015[Crossref], [PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhvVCjtbk%253D&md5=ddc6b561e337cbf0ee09d7a4bc546004Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: Implications for multiple sclerosisStorer, Paul D.; Xu, Jihong; Chavis, Janet; Drew, Paul D.Journal of Neuroimmunology (2005), 161 (1-2), 113-122CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)Peroxisome proliferator-activated receptor (PPAR)-γ agonists, including thiazolidinediones (TZDs) and 15-deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2), have been shown to be effective in the treatment of exptl. autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). This study aimed to compare the anti-inflammatory actions of three TZDs - rosiglitazone, pioglitazone, and ciglitazone - with those of 15d-PGJ2 on stimulated mouse microglia and astrocytes. The results show that TZDs and 15d-PGJ2 are effective in inhibiting prodn. of nitric oxide, the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, and the chemokine MCP-1 from microglia and astrocytes. However, 15d-PGJ2 was a more potent suppressor of pro-inflammatory activity than the TZDs. These studies suggest that PPAR-γ agonists modulate EAE, at least in part, by inhibiting the activation of microglia and astrocytes. The studies further suggest that PPAR-γ agonists may be effective in the treatment of MS.
- 95Zhang, F.; Liu, F.; Yan, M.; Ji, H.; Hu, L.; Li, X.; Qian, J.; He, X.; Zhang, L.; Shen, A.; Cheng, C. Peroxisome Proliferator-Activated Receptor-γ Agonists Suppress INOS Expression Induced by LPS in Rat Primary Schwann Cells. J. Neuroimmunol. 2010, 218 (1–2), 36– 47, DOI: 10.1016/j.jneuroim.2009.10.016[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtlyrtg%253D%253D&md5=61703c8257cd0c29eb7300445325ddc5Peroxisome proliferator-activated receptor-γ agonists suppress iNOS expression induced by LPS in rat primary Schwann cellsZhang, Fupeng; Liu, Fen; Yan, Meijuan; Ji, Huoyan; Hu, Ling; Li, Xiaohong; Qian, Ji; He, Xingxin; Zhang, Li; Shen, Aiguo; Cheng, ChunJournal of Neuroimmunology (2010), 218 (1-2), 36-47CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)In bacterial-induced peripheral nervous system (PNS) inflammation, Schwann cells (SCs) are activated, producing inducible nitric oxide synthase (iNOS), contributed to the pathogenesis of demyelinating disease, such as multiple sclerosis. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) has been shown to play a protective role in cellular inflammatory responses. Here the authors showed that LPS-induced iNOS biosynthesis was in a concn. and time-dependent manner. In LPS-treated primary SCs, re-treatment with PPAR-γ agonist remitted the increase of iNOS, p38 phosphorylation and TLR4, MyD88, augmented the expression of PPAR-γ and localization in nuclear. Coadministration of GW 9662 reversed the effect of PPAR-γ agonists. These results suggest that PPAR-γ agonists, 15d-PGJ2 and pioglitazone, had the anti-inflammatory effects.
- 96Grajchen, E.; Wouters, E.; Van De Haterd, B.; Haidar, M.; Hardonnière, K.; Dierckx, T.; Van Broeckhoven, J.; Erens, C.; Hendrix, S.; Kerdine-Römer, S.; Hendriks, J. J. A.; Bogie, J. F. J. CD36-Mediated Uptake of Myelin Debris by Macrophages and Microglia Reduces Neuroinflammation. J. Neuroinflammation 2020, 17, 224, DOI: 10.1186/s12974-020-01899-x[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFSitrnJ&md5=ae51e4155d73f19f3005bef24cb23b9bCD36-mediated uptake of myelin debris by macrophages and microglia reduces neuroinflammationGrajchen, Elien; Wouters, Elien; van de Haterd, Britt; Haidar, Mansour; Hardonniere, Kevin; Dierckx, Tess; Van Broeckhoven, Jana; Erens, Celine; Hendrix, Sven; Kerdine-Romer, Saadia; Hendriks, Jerome J. A.; Bogie, Jeroen F. J.Journal of Neuroinflammation (2020), 17 (1), 224CODEN: JNOEB3; ISSN:1742-2094. (BioMed Central Ltd.)The presence of foamy macrophages and microglia contg. intracellular myelin remnants is a pathol. hallmark of neurodegenerative disorders such as multiple sclerosis (MS). Despite the importance of myelin internalization in affecting both central nervous system repair and neuroinflammation, the receptors involved in myelin clearance and their impact on the phagocyte phenotype and lesion progression remain to be clarified. Flow cytometry, quant. PCR, and immunohistochem. were used to define the mRNA and protein abundance of CD36 in myelin-contg. phagocytes. The impact of CD36 and nuclear factor erythroid 2-related factor 2 (NRF2) on the phagocytic and inflammatory features of macrophages and microglia was assessed using a pharmacol. CD36 inhibitor (sulfo-N-succinimidyl oleate) and Nrf2-/- bone marrow-derived macrophages. Finally, the exptl. autoimmune encephalomyelitis (EAE) model was used to establish the impact of CD36 inhibition on neuroinflammation and myelin phagocytosis in vivo. Here, we show that the fatty acid translocase CD36 is required for the uptake of myelin debris by macrophages and microglia, and that myelin internalization increased CD36 expression through NRF2. Pharmacol. inhibition of CD36 promoted the inflammatory properties of myelin-contg. macrophages and microglia in vitro, which was paralleled by a reduced activity of the anti-inflammatory lipid-sensing liver X receptors and peroxisome proliferator-activated receptors. By using the EAE model, we provide evidence that CD36 is essential for myelin debris clearance in vivo. Importantly, CD36 inhibition markedly increased the neuroinflammatory burden and disease severity in the EAE model. Altogether, we show for the first time that CD36 is crucial for clearing myelin debris and suppressing neuroinflammation in demyelinating disorders such as MS.
- 97Schmidt, S.; Moric, E.; Schmidt, M.; Sastre, M.; Feinstein, D. L.; Heneka, M. T. Anti-Inflammatory and Antiproliferative Actions of PPAR-γ Agonists on T Lymphocytes Derived from MS Patients. J. Leukocyte Biol. 2004, 75 (3), 478– 485, DOI: 10.1189/jlb.0803402[Crossref], [PubMed], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXis1ehs7s%253D&md5=00d6f031765057f7e72be94b36e28365Anti-inflammatory and antiproliferative actions of PPAR-γ agonists on T lymphocytes derived from MS patientsSchmidt, Stephan; Moric, Edin; Schmidt, Martina; Sastre, Magdalena; Feinstein, Douglas L.; Heneka, Michael T.Journal of Leukocyte Biology (2004), 75 (3), 478-485CODEN: JLBIE7; ISSN:0741-5400. (Federation of American Societies for Experimental Biology)Peroxisomal proliferator-activated receptors (PPARs) belong to a nuclear receptor superfamily of ligand-activated transcription factors. The PPAR-γ isoform is expressed in human T lymphocytes, and oral administration of PPAR-γ agonists ameliorates the clin. course and histopathol. features in exptl. autoimmune encephalomyelitis, an animal model for multiple sclerosis, suggesting a potential role for PPAR-γ agonists in the treatment of autoimmune diseases. To assess a potential therapeutic role of PPAR-γ agonists in multiple sclerosis, we compared the immunomodulatory effects of the thiazolidinedione (TZD) drugs pioglitazone (PIO) and ciglitazone and the non-TZD PPAR-γ agonist GW347845 on human T leukemia cells (Jurkat cells) and phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) derived from 21 multiple sclerosis patients and 12 healthy donors. PIO, ciglitazone, and GW347845 suppressed PHA-induced T cell proliferation by 40-50% and secretion of interferon-γ and tumor necrosis factor α, by 30-50%. Inhibition of proliferation was increased to ∼80% and that of proinflammatory cytokine secretion, to 80-90% when PBMCs were first preincubated with PPAR-γ agonists and re-exposed at the time of PHA stimulation, indicating a sensitizing effect of PPAR-γ agonists. Inhibition of proliferation was also obsd. in the tetanus toxoid-specific T cell line KHS.TT2, albeit to a lesser extent. The antiproliferative effects of PIO and GW347845 were accompanied by a decrease of cell viability. Electron microscopy and Western blot anal. revealed DNA condensation and down-regulation of bcl-2, suggesting the induction of apoptosis in activated T lymphocytes. In summary, the data support the potential use of PPAR-γ agonists as immunomodulatory, therapeutic agents for autoimmune diseases.
- 98Polak, P. E.; Kalinin, S.; Dello Russo, C.; Gavrilyuk, V.; Sharp, A.; Peters, J. M.; Richardson, J.; Willson, T. M.; Weinberg, G.; Feinstein, D. L. Protective Effects of a Peroxisome Proliferator-Activated Receptor-β/δ Agonist in Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 2005, 168 (1–2), 65– 75, DOI: 10.1016/j.jneuroim.2005.07.006[Crossref], [PubMed], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVynt7bJ&md5=6cfd07b1f8b870cf47361a68e1758c12Protective effects of a peroxisome proliferator-activated receptor-β/δ agonist in experimental autoimmune encephalomyelitisPolak, Paul E.; Kalinin, Sergey; Dello Russo, Cinzia; Gavrilyuk, Vitaliy; Sharp, Anthony; Peters, Jeffrey M.; Richardson, Jill; Willson, Tim M.; Weinberg, Guy; Feinstein, Douglas L.Journal of Neuroimmunology (2005), 168 (1-2), 65-75CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)Agonists of the peroxisome proliferator-activated receptor gamma (PPARγ) exert anti-inflammatory and anti-proliferative effects which led to testing of these drugs in exptl. autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. In contrast, the effect of PPAR delta (PPARδ) agonists in EAE is not yet known. We show that oral administration of the selective PPARδ agonist GW0742 reduced clin. symptoms in C57BL/6 mice that had been immunized with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide. In contrast to previous results with PPARγ agonists, GW0742 only modestly attenuated clin. symptoms when the drug was provided simultaneously with immunization, but a greater redn. was obsd. if administered during disease progression. Reduced clin. symptoms were accompanied by a redn. in the appearance of new cortical lesions, however cerebellar lesion load was not reduced. Treatment of T-cells with GW0742 either in vivo or in vitro did not reduce IFNγ prodn.; however GW0742 reduced astroglial and microglial inflammatory activation and IL-1β levels in EAE brain. RTPCR anal. showed that GW0742 increased expression of some myelin genes. These data demonstrate that PPARδ agonists, like other PPAR ligands, can exert protective actions in an autoimmune model of demyelinating disease.
- 99Kanakasabai, S.; Walline, C. C.; Chakraborty, S.; Bright, J. J. PPARδ Deficient Mice Develop Elevated Th1/Th17 Responses and Prolonged Experimental Autoimmune Encephalomyelitis. Brain Res. 2011, 1376, 101– 112, DOI: 10.1016/j.brainres.2010.12.059[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhvFektLc%253D&md5=0ff2f2283a6aff09c3c0e9a5f0c59d2cPPARδ deficient mice develop elevated Th1/Th17 responses and prolonged experimental autoimmune encephalomyelitisKanakasabai, Saravanan; Walline, Crystal C.; Chakraborty, Sharmistha; Bright, John J.Brain Research (2011), 1376 (), 101-112CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)Multiple sclerosis (MS) is a neurol. disorder that affects more than a million people worldwide. The etiol. of MS is not known and there is no medical treatment that can cure MS. Earlier studies have shown that peroxisome proliferator-activated receptor (PPARs) agonists ameliorate MS-like disease in exptl. allergic encephalomyelitis (EAE). In this study the authors have used PPARδ deficient mice to det. its physiol. role in the regulation of CNS EAE and MS. The authors found that PPARδ-/- mice develop EAE with similar day of onset and disease incidence compared to C57BL/6 wild type mice. Interestingly, both male and female PPARδ-/- mice showed prolonged EAE with resistance to remission and recovery. PPARδ-/- mice with EAE expressed elevated levels of IFNγ and IL-17 along with IL-12p35 and IL-12p40 in the brain and spleen. PPARδ-/- mice also developed augmented neural antigen-specific Th1/Th17 responses and impaired Th2/Treg responses compared to wild type mice. These findings indicate that PPARδ-/- mice develop prolonged EAE in assocn. with augmented Th1/Th17 responses, suggesting a crit. physiol. role for PPARδ in the remission and recovery of EAE.
- 100Defaux, A.; Zurich, M. G.; Braissant, O.; Honegger, P.; Monnet-Tschudi, F. Effects of the PPAR-β Agonist GW501516 in an in Vitro Model of Brain Inflammation and Antibody-Induced Demyelination. J. Neuroinflammation 2009, 6, 15, DOI: 10.1186/1742-2094-6-15[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MzntlGguw%253D%253D&md5=ce8d6428111ad1e56400c1ae04293d95Effects of the PPAR-beta agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelinationDefaux Antoinette; Zurich Marie-Gabrielle; Braissant Olivier; Honegger Paul; Monnet-Tschudi FlorianneJournal of neuroinflammation (2009), 6 (), 15 ISSN:.BACKGROUND: Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-beta seems to play an important role in the regulation of central inflammation. In addition, PPAR-beta agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-beta agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-gamma and LPS. METHODS: Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-gamma and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG). The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), inducible NO synthase (i-NOS), PPAR-beta, PPAR-gamma, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and high molecular weight neurofilament protein (NF-H). GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4) and ED1 labeling. RESULTS: GW 501516 decreased the IFN-gamma-induced up-regulation of TNF-alpha and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-beta agonist. However, it increased IL-6 m-RNA expression. In demyelinating cultures, reactivity of both microglial cells and astrocytes was observed, while the expression of the inflammatory cytokines and iNOS remained unaffected. Furthermore, GW 501516 did not protect against the demyelination-induced changes in gene expression. CONCLUSION: Although GW 501516 showed anti-inflammatory activity, it did not protect against antibody-mediated demyelination. This suggests that the protective effects of PPAR-beta agonists observed in vivo can be attributed to their anti-inflammatory properties rather than to a direct protective or trophic effect on oligodendrocytes.
- 101Kanakasabai, S.; Chearwae, W.; Walline, C. C.; Iams, W.; Adams, S. M.; Bright, J. J. Peroxisome Proliferator-Activated Receptor δ Agonists Inhibit T Helper Type 1 (Th1) and Th17 Responses in Experimental Allergic Encephalomyelitis. Immunology 2010, 130 (4), 572– 588, DOI: 10.1111/j.1365-2567.2010.03261.x[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvVWnsLc%253D&md5=efd42469ce5c7f751064c5a0b1d03029Peroxisome proliferator-activated receptor δ agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitisKanakasabai, Saravanan; Chearwae, Wanida; Walline, Crystal C.; Iams, Wade; Adams, Suzanne M.; Bright, John J.Immunology (2010), 130 (4), 572-588CODEN: IMMUAM; ISSN:0019-2805. (Wiley-Blackwell)Multiple sclerosis (MS) is a neurol. disorder that affects more than a million people world-wide. The etiol. of MS is not known and there is no medical treatment available that can cure MS. Exptl. autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease model of MS. The pathogenesis of EAE/MS is a complex process involving activation of immune cells, secretion of inflammatory cytokines and destruction of myelin sheath in the central nervous system (CNS). Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptor transcription factors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown that PPARγ, α and δ agonists inhibit CNS inflammation and demyelination in the EAE model of MS. In this study we show that the PPARδ agonists GW501516 and L165041 ameliorate MOGp35-55-induced EAE in C57BL/6 mice by blocking interferon (IFN)-γ and interleukin (IL)-17 prodn. by T helper type 1 (Th1) and Th17 cells. The inhibition of EAE by PPARδ agonists was also assocd. with a decrease in IL-12 and IL-23 and an increase in IL-4 and IL-10 expression in the CNS and lymphoid organs. These findings indicate that PPARδ agonists modulate Th1 and Th17 responses in EAE and suggest their use in the treatment of MS and other autoimmune diseases.
- 102Jana, M.; Mondal, S.; Gonzalez, F. J.; Pahan, K. Gemfibrozil, a Lipid-Lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-Activated Receptor-β. J. Biol. Chem. 2012, 287 (41), 34134– 34148, DOI: 10.1074/jbc.M112.398552[Crossref], [PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVKlsLjK&md5=c48696a5867211d0b2f69ac1ce28fe46Gemfibrozil, a Lipid-lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-activated Receptor-βJana, Malabendu; Mondal, Susanta; Gonzalez, Frank J.; Pahan, KalipadaJournal of Biological Chemistry (2012), 287 (41), 34134-34148CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis. Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identified another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (myelin basic protein, myelin oligodendrocyte glycoprotein, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, and proteolipid protein (PLP)) in primary human oligodendrocytes, mixed glial cells, and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-α (PPAR-α), we were unable to detect PPAR-α in either gemfibrozil-treated or untreated human oligodendrocytes, and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-α(-/-) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-β but not PPAR-γ. Consistently, antisense knockdown of PPAR-β, but not PPAR-γ, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not up-regulate myelin genes in oligodendroglia isolated from PPAR-β(-/-) mice. Chromatin immunopptn. anal. showed that gemfibrozil induced the recruitment of PPAR-β to the promoter of PLP and myelin oligodendrocyte glycoprotein genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-β to the PLP promoter in vivo in the spinal cord of exptl. autoimmune encephalomyelitis mice and suppression of exptl. autoimmune encephalomyelitis symptoms in PLP-T cell receptor transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-β and that gemfibrozil, a prescribed drug for humans, may find further therapeutic use in demyelinating diseases.
- 103Sakuma, S.; Endo, T.; Kanda, T.; Nakamura, H.; Yamasaki, S.; Yamakawa, T. Synthesis of a Novel Human PPARδ Selective Agonist and Its Stimulatory Effect on Oligodendrocyte Differentiation. Bioorg. Med. Chem. Lett. 2011, 21 (1), 240– 244, DOI: 10.1016/j.bmcl.2010.11.030[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Sqsb7J&md5=3a7d74f2f007c601a273b75699478f26Synthesis of a novel human PPARδ selective agonist and its stimulatory effect on oligodendrocyte differentiationSakuma, Shogo; Endo, Tsuyoshi; Kanda, Takashi; Nakamura, Hideki; Yamasaki, Satomi; Yamakawa, TomioBioorganic & Medicinal Chemistry Letters (2011), 21 (1), 240-244CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A novel peroxisome proliferator-activated receptor (PPAR)δ selective agonist with a characteristic benzisoxazole ring, I, was successfully synthesized. Compd. I exhibited potent human PPARδ transactivation activity and high δ selectivity. Further, it stimulated differentiation of primary oligodendrocyte precursor cells in vitro, indicating that it may be an effective drug in the treatment of demyelinating disorders such as multiple sclerosis.
- 104Kaiser, C. C.; Shukla, D. K.; Stebbins, G. T.; Skias, D. D.; Jeffery, D. R.; Stefoski, D.; Katsamakis, G.; Feinstein, D. L. A Pilot Test of Pioglitazone as an Add-on in Patients with Relapsing Remitting Multiple Sclerosis. J. Neuroimmunol. 2009, 211 (1–2), 124– 130, DOI: 10.1016/j.jneuroim.2009.04.011[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnt1Gktb0%253D&md5=e699f96e3ce6499a1430f31edeefb082A pilot test of pioglitazone as an add-on in patients with relapsing remitting multiple sclerosisKaiser, Claudia C.; Shukla, Dinesh K.; Stebbins, Glenn T.; Skias, Demetrios D.; Jeffery, Douglas R.; Stefoski, Dusan; Katsamakis, George; Feinstein, Douglas L.Journal of Neuroimmunology (2009), 211 (1-2), 124-130CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)The peroxisome proliferator-activated receptor gamma agonist pioglitazone is FDA-approved for treatment of type-2 diabetes due to insulin sensitizing effects. However pioglitazone has anti-inflammatory and neuroprotective effects, reduces glial and T-cell activation, and reduces signs in an animal model of multiple sclerosis (MS). We tested the effects of daily treatment with pioglitazone in a small cohort of relapsing remitting MS patients. RRMS patients taking IFNβ-1α and having an EDSS score < 6.5 were randomized to treatment with pioglitazone (30 mg daily, p.o.) or placebo and monitored clin. and by MRI for 1 yr. Primary outcomes were safety and tolerability, secondary outcomes included changes in neurol. outcome, lesion burden, and gray matter vol. After 1 yr 11 patients in the pioglitazone arm and 10 in the placebo arm completed the trial. Pioglitazone was well tolerated with a similar incidence of non-serious adverse events in placebo and treatment groups. After 1 yr there were no significant differences in clin. symptoms as assessed by EDSS; however MRI showed a significant redn. in gray matter atrophy, and a trend for reduced lesion burden in the treatment group. These results show that pioglitazone was well tolerated in RRMS patients with indications of beneficial effects, warranting further trials to establish clin. efficacy.
- 105Shukla, D. K.; Kaiser, C. C.; Stebbins, G. T.; Feinstein, D. L. Effects of Pioglitazone on Diffusion Tensor Imaging Indices in Multiple Sclerosis Patients. Neurosci. Lett. 2010, 472 (3), 153– 156, DOI: 10.1016/j.neulet.2010.01.046[Crossref], [PubMed], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjt1ers78%253D&md5=44355f921438e3ed0d58aace2043cf44Effects of pioglitazone on diffusion tensor imaging indices in multiple sclerosis patientsShukla, Dinesh K.; Kaiser, Claudia C.; Stebbins, Glenn T.; Feinstein, Douglas L.Neuroscience Letters (2010), 472 (3), 153-156CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Pioglitazone is an FDA-approved peroxisome proliferator activated receptor gamma (PPARγ) agonist. We tested the hypothesis that treatment with pioglitazone reduces new lesion development in patients with RRMS. Twenty-two patients were treated with pioglitazone or placebo and monitored by diffusion tensor imaging (DTI) at baseline and after 12 mo. A neg. correlation was found between the 1-yr change in relative anisotropy (RA) and fluid attenuated inversion recovery (FLAIR) lesion burden in the pioglitazone group. Regions of interest (ROIs) having high ADC and low RA values at baseline had a significantly higher chance to develop into lesions in the placebo group than similar ROIs in the pioglitazone group. These findings suggest that baseline DTI parameters can provide a prognostic surrogate marker for lesions, and that pioglitazone can reduce conversion of normal appearing white matter to lesions.
- 106Negrotto, L.; Farez, M. F.; Correale, J. Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis. JAMA Neurol. 2016, 73 (5), 520– 528, DOI: 10.1001/jamaneurol.2015.4807[Crossref], [PubMed], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jotFCrug%253D%253D&md5=421d790edbbc6237084f3a13568705e1Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple SclerosisNegrotto Laura; Farez Mauricio F; Correale JorgeJAMA neurology (2016), 73 (5), 520-8 ISSN:.IMPORTANCE: Metabolic syndrome (MetS) is thought to influence several autoimmune diseases, including multiple sclerosis (MS). Anti-inflammatory effects of treatments used for MetS, such as metformin hydrochloride and pioglitazone hydrochloride, have been demonstrated, although clinical evidence supporting use of these treatments in MS is lacking. OBJECTIVES: To determine whether metformin and/or pioglitazone are associated with a reduction in disease activity as measured by brain magnetic resonance imaging in patients with MS and MetS and to evaluate the potential mechanisms underlying this anti-inflammatory effect. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted from March 1, 2012, to December 30, 2014, at a private MS referral center among 50 obese patients with MS who also developed MetS. Twenty patients received metformin hydrochloride, 850 to 1500 mg/d, and 10 patients received pioglitazone hydrochloride, 15 to 30 mg/d; 20 untreated patients served as controls. Groups were comparable in terms of sex, age, body mass index, Expanded Disability Status Scale score, disease duration, annual relapse rate, and treatment status. Patients were followed up for a mean (SD) of 26.7 (2.7) months (range, 24-33 months). MAIN OUTCOMES AND MEASURES: Magnetic resonance imaging of the brain was performed at 6-month intervals, and the presence of new or enlarging T2 lesions or gadolinium-enhancing lesions was registered. Serum leptin and adiponectin levels were measured. The production of cytokines by peripheral blood mononuclear cells was assayed, as were regulatory T-cell numbers and function. RESULTS: Of 50 patients, after 6 months of treatment, 20 patients with MS who were treated with metformin and 10 who received pioglitazone showed a significant decrease in the number of new or enlarging T2 lesions (metformin, 2.5 at study entry to 0.5 at month 24; pioglitazone, 2.3 at study entry to 0.6 at month 24), as well as of gadolinium-enhancing lesions (metformin, 1.8 at study entry to 0.1 at month 24; pioglitazone, 2.2 at study entry to 0.3 at month 24). Compared with controls, both treatments led to a decrease in mean (SD) leptin levels (metformin, 5.5 [2.4] vs 10.5 [3.4] ng/mL, P < .001; pioglitazone, 4.1 [0.8] vs 11.0 [2.6] ng/mL, P < .001) and increase in mean (SD) adiponectin serum levels (metformin, 15.4 [5.5] vs 4.5 [2.4] μg/mL, P < .001; pioglitazone, 12.6 [3.6] vs 4.8 [0.6] μg/mL, P < .001). Mean (SD) number of myelin basic protein peptide-specific cells secreting interferon γ and interleukin (IL)-17 were significantly reduced in patients receiving metformin compared with controls (interferon γ, 30.3 [11.5] vs 82.8 [18.8], P < .001; IL-17, 212.4 [85.5] vs 553.8 [125.9], P < .001). Patients treated with pioglitazone showed significant decreases in the mean (SD) number of myelin basic protein peptide-specific cells secreting IL-6 and tumor necrosis factor compared with controls (IL-6, 361.6 [80.5] vs 1130.7 [149.21], P < .001; tumor necrosis factor, 189.9 [53.4] vs 341.0 [106.0], P < .001). Both metformin and pioglitazone resulted in a significant increase in the number and regulatory functions of CD4+CD25+FoxP3+ regulatory T cells compared with controls (metformin, 6.7 [1.5] vs 2.1 [1.0], P = .001; pioglitazone, 6.9 [0.8] vs 3.0 [0.8], P = .001). CONCLUSIONS AND RELEVANCE: Treatment with metformin and pioglitazone has beneficial anti-inflammatory effects in patients with MS and MetS and should be further explored.
- 107Ratziu, V.; Harrison, S. A.; Francque, S.; Bedossa, P.; Lehert, P.; Serfaty, L.; Romero-Gomez, M.; Boursier, J.; Abdelmalek, M.; Caldwell, S.; Drenth, J.; Anstee, Q. M.; Hum, D.; Hanf, R.; Roudot, A.; Megnien, S.; Staels, B.; Sanyal, A. Elafibranor, an Agonist of the Peroxisome Proliferator–Activated Receptor−α and – δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology 2016, 150 (5), 1147– 1159, DOI: 10.1053/j.gastro.2016.01.038[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xms1Klu7g%253D&md5=cee5c53be700bd0a9eadb455390a222cElafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis WorseningRatziu, Vlad; Harrison, Stephen A.; Francque, Sven; Bedossa, Pierre; Lehert, Philippe; Serfaty, Lawrence; Romero-Gomez, Manuel; Boursier, Jerome; Abdelmalek, Manal; Caldwell, Steve; Drenth, Joost; Anstee, Quentin M.; Hum, Dean; Hanf, Remy; Roudot, Alice; Megnien, Sophie; Staels, Bart; Sanyal, ArunGastroenterology (2016), 150 (5), 1147-1159.e5CODEN: GASTAB; ISSN:0016-5085. (Elsevier)Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-δ. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metab. and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with nonalcoholic steatohepatitis (NASH). Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n = 93), elafibranor 120 mg (n = 91), or placebo (n = 92) each day for 52 wk at sites in Europe and the United States. Clin. and lab. evaluations were performed every 2 mo during this 1-yr period. Liver biopsies were then collected and patients were assessed 3 mo later. The primary outcome was resoln. of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver disease activity score. In intention-to-treat anal., there was no significant difference between the elafibranor and placebo groups in the protocol-defined primary outcome. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranor group vs the placebo group (19% vs 12%; odds ratio = 2.31; 95% confidence interval: 1.02-5.24; P = .045), based on a post-hoc anal. for the modified definition. In post-hoc analyses of patients with nonalcoholic fatty liver disease activity score ≥4 (n = 234), elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; odds ratio = 3.16; 95% confidence interval: 1.22-8.13; P = .018) and the modified definitions (19% vs 9%; odds ratio = 3.52; 95% confidence interval: 1.32-9.40; P = .013). Patients with NASH resoln. after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resoln. (mean redn. of 0.65 ± 0.61 in responders for the primary outcome vs an increase of 0.10 ± 0.98 in nonresponders; P < .001). Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group vs the placebo group. Elafibranor was well tolerated and did not cause wt. gain or cardiac events, but did produce a mild, reversible increase in serum creatinine (effect size vs placebo: increase of 4.31 ± 1.19 μmol/L; P < .001). A post-hoc anal. of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 yr) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat anal. and in patients with moderate or severe NASH. However, the predefined end point was not met in the intention to treat population. Elafibranor was well tolerated and improved patients' cardiometabolic risk profile. ClinicalTrials.gov no.: NCT01694849.
- 108Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown, K. K.; Cobb, J. E.; Collins, J. L.; Harrington, W. W.; Hashim, M. A.; Hull-Ryde, E. A.; Kaldor, I.; Kliewer, S. A.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J. M.; Lenhard, J. M.; Orband-Miller, L. A.; Miller, J. F.; Mook, R. A.; Noble, S. A.; Oliver, W.; Parks, D. J.; Plunket, K. D.; Szewczyk, J. R.; Willson, T. M. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 1. Discovery of a Novel Series of Potent Antihyperglycemic and Antihyperlipidemic Agents. J. Med. Chem. 1998, 41 (25), 5020– 5036, DOI: 10.1021/jm9804127[ACS Full Text], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntF2ru7w%253D&md5=712246afde03c871a967800db615ba9fN-(2-Benzoylphenyl)-L-tyrosine PPARγ Agonists. 1. Discovery of a Novel Series of Potent Antihyperglycemic and Antihyperlipidemic AgentsHenke, Brad R.; Blanchard, Steven G.; Brackeen, Marcus F.; Brown, Kathleen K.; Cobb, Jeff E.; Collins, Jon L.; Harrington, W. Wallace, Jr.; Hashim, Mir A.; Hull-Ryde, Emily A.; Kaldor, Istvan; Kliewer, Steven A.; Lake, Debra H.; Leesnitzer, Lisa M.; Lehmann, Juergen M.; Lenhard, James M.; Orband-Miller, Lisa A.; Miller, John F.; Mook, Robert A.; Noble, Stewart A.; Oliver, William; Parks, Derek J.; Plunket, Kelli D.; Szewczyk, Jerzy R.; Willson, Timothy M.Journal of Medicinal Chemistry (1998), 41 (25), 5020-5036CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivs. which are potent, selective PPARγ agonists. Through the use of in vitro PPARγ binding and functional assays, (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)amino)propionic acid (I) was identified as a structurally novel PPARγ agonist. Structure-activity relationships identified the 2-aminobenzophenone moiety as a suitable isostere for the chem. labile enaminone moiety in I, affording 2-((2-benzoylphenyl)amino)-3-(4-(benzyloxy)phenyl)propionic acid. Replacement of the benzyl group in 9 with substituents known to confer in vivo potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARγ, affording a series of potent and selective PPARγ agonists exemplified by (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(methylpyridin-2-ylamino)ethoxy]phenyl}propionic acid (II), 3-{4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl}-(2S)-((2-benzoylphenyl)amino)propanoic acid, and (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic acid (III). II and III show potent antihyperglycemic and antihyperlipidemic activity when given orally in two rodent models of type 2 diabetes. In addn., these analogs are readily prepd. in chiral nonracemic fashion from L-tyrosine and do not show a propensity to undergo racemization in vitro. The increased potency of these PPARγ agonists relative to troglitazone may translate into superior clin. efficacy for the treatment of type 2 diabetes.
- 109Cobb, J. E.; Blanchard, S. G.; Boswell, E. G.; Brown, K. K.; Charifson, P. S.; Cooper, J. P.; Collins, J. L.; Dezube, M.; Henke, B. R.; Hull-Ryde, E. A.; Lake, D. H.; Lenhard, J. M.; Oliver, W.; Oplinger, J.; Pentti, M.; Parks, D. J.; Plunket, K. D.; Tong, W.-Q. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 3. Structure-Activity Relationship and Optimization of the N-Aryl Substituent. J. Med. Chem. 1998, 41 (25), 5055– 5069, DOI: 10.1021/jm980414r[ACS Full Text], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntFegu74%253D&md5=c411bc54b96bdd80f365c2300572f7b1N-(2-Benzoylphenyl)-L-tyrosine PPARγ Agonists. 3. Structure-Activity Relationship and Optimization of the N-Aryl SubstituentCobb, Jeff E.; Blanchard, Steven G.; Boswell, Evan G.; Brown, Kathleen K.; Charifson, Paul S.; Cooper, Joel P.; Collins, Jon L.; Dezube, Milana; Henke, Brad R.; Hull-Ryde, Emily A.; Lake, Debra H.; Lenhard, James M.; Oliver, William, Jr.; Oplinger, Jeffery; Pentti, Mila; Parks, Derek J.; Plunket, Kelli D.; Tong, Wei-QinJournal of Medicinal Chemistry (1998), 41 (25), 5055-5069CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)3-{4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl}-(2S)-((2-benzoylphenyl)amino)propionic acid (I) and (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid (II) are peroxisome proliferator-activated receptor γ (PPARγ) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of I and II, a series of novel carboxylic acid analogs, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARγ agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of I and II are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two Ph rings of this moiety. Addn. of substituents to this moiety generally produced compds. that are less active in the cell-based functional assays of PPARγ activity although binding affinity to PPARγ may be maintained. A particularly promising set of analogs is the anthranilic acid esters in which the Ph ring in the 2-benzoyl group of I and II has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid Me ester (III) has a pKi of 8.43 in the binding assay using human PPARγ ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARγ activity. Finally, III was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.
- 110Collins, J. L.; Blanchard, S. G.; Boswell, G. E.; Charifson, P. S.; Cobb, J. E.; Henke, B. R.; Hull-Ryde, E. A.; Kazmierski, W. M.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J.; Lenhard, J. M.; Orband-Miller, L. A.; Gray-Nunez, Y.; Parks, D. J.; Plunkett, K. D.; Tong, W.-Q. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 2. Structure-Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety. J. Med. Chem. 1998, 41 (25), 5037– 5054, DOI: 10.1021/jm980413z[ACS Full Text], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntFegurc%253D&md5=10c2016d15446cb8bfa5d1eba6a2558bN-(2-Benzoylphenyl)-L-tyrosine PPARγ Agonists. 2. Structure-Activity Relationship and Optimization of the Phenyl Alkyl Ether MoietyCollins, Jon L.; Blanchard, Steven G.; Boswell, G. Evan; Charifson, Paul S.; Cobb, Jeff E.; Henke, Brad R.; Hull-Ryde, Emily A.; Kazmierski, Wieslaw M.; Lake, Debra H.; Leesnitzer, Lisa M.; Lehmann, Juergen; Lenhard, James M.; Orband-Miller, Lisa A.; Gray-Nunez, Yolanda; Parks, Derek J.; Plunkett, Kelli D.; Tong, Wei-QinJournal of Medicinal Chemistry (1998), 41 (25), 5037-5054CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic acid (I) (PPARγ pKi = 8.94, PPARγ pEC50 = 9.47) as a potent and selective PPARγ agonist. We now report the expanded structure-activity relationship around the Ph alkyl ether moiety by pursuing both a classical medicinal chem. approach and a solid-phase chem. approach for analog synthesis. The soln.-phase strategy focused on evaluating the effects of oxazole and Ph ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of I with several replacements providing potent and selective PPARγ agonists with improved aq. soly. Specifically, replacement of the Ph ring of the phenyloxazole moiety with a 4-pyridyl group to give (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-pyridin-4-yloxazol-4-yl)ethoxy]phenyl}propionic acid (PPARγ pKi = 8.85, PPARγ pEC50 = 8.74) or a 4-methylpiperazine to give (2S)-((2-benzoylphenyl)amino)-3-(4-{2-[5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl]ethoxy}phenyl)propionic acid (PPARγ pKi = 8.66, PPARγ pEC50 = 8.89) provided two potent and selective PPARγ agonists with increased soly. in pH 7.4 phosphate buffer and simulated gastric fluid as compared to I. The second strategy took advantage of the speed and ease of parallel solid-phase analog synthesis to generate a more diverse set of Ph alkyl ethers which led to the identification of a no. of novel, high-affinity PPARγ ligands (PPARγ pKi's 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPARγ binding, functional activity, selectivity, and aq. soly.
- 111Berger, J.; Leibowitz, M. D.; Doebber, T. W.; Elbrecht, A.; Zhang, B.; Zhou, G.; Biswas, C.; Cullinan, C. A.; Hayes, N. S.; Li, Y.; Tanen, M.; Ventre, J.; Wu, M. S.; Berger, G. D.; Mosley, R.; Marquis, R.; Santini, C.; Sahoo, S. P.; Tolman, R. L.; Smith, R. G.; M?ller, D. E. Novel Peroxisome Proliferator-Activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects. J. Biol. Chem. 1999, 274 (10), 6718– 6725, DOI: 10.1074/jbc.274.10.6718[Crossref], [PubMed], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXhs1ektb0%253D&md5=c62b5d778386a81d91221d6330f8e8d3Novel peroxisome proliferator-activated receptor (PPAR) γ and PPARδ ligands produce distinct biological effectsBerger, Joel; Leibowitz, Mark D.; Doebber, Thomas W.; Elbrecht, Alex; Zhang, Bei; Zhou, Gaochou; Biswas, Chhabi; Cullinan, Catherine A.; Hayes, Nancy S.; Li, Ying; Tanen, Michael; Ventre, John; Wu, Margaret S.; Berger, Gregory D.; Mosley, Ralph; Marquis, Robert; Santini, Conrad; Sahoo, Soumya P.; Tolman, Richard L.; Smith, Roy G.; Moller, David E.Journal of Biological Chemistry (1999), 274 (10), 6718-6725CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The peroxisome proliferator-activated receptors (PPARs) include three receptor subtypes encoded by sep. genes: PPARα, PPARδ, and PPARγ. PPARγ has been implicated as a mediator of adipocyte differentiation and the mechanism by which thiazolidinedione drugs exert in vivo insulin sensitization. Here we characterized novel, non-thiazolidinedione agonists for PPARγy and PPARδ that were identified by radioligand binding assays. In transient transactivation assays these ligands were agonists of the receptors to which they bind. Protease protection studies showed that ligand binding produced specific alterations in receptor conformation. Both PPARγ and PPARδ directly interacted with a nuclear receptor co-activator (CREB-binding protein) in an agonist-dependent manner. Only the PPARγ agonists were able to promote differentiation of 3T3-L1 preadipocytes. In diabetic db/db mice all PPARγ agonists were orally active insulin-sensitizing agents producing redns. of elevated plasma glucose and triglyceride concns. In contrast, selective in vivo activation of PPARδ did not significantly affect these parameters. In vivo PPARα activation with WY-14653 resulted in redns. in elevated triglyceride levels with minimal effect on hyperglycemia. We conclude that: 1. synthetic non-thiazolidinediones can serve as ligands of PPARγ and PPARδ; 2. ligand-dependent activation of PPARδ involves an apparent conformational change and assocn. of the receptor ligand binding domain with CREB-binding protein; 3. PPARγ activation (but not PPARδ or PPARα activation) is sufficient to potentiate preadipocyte differentiation; 4. non-thiazolidinedione PPARγ agonists improve hyperglycemia and hypertriglyceridemia in vivo; 5. although PPARα activation is sufficient to affect triglyceride metab., PPARδ activation does not appear to modulate glucose or triglyceride levels.
- 112Brown, P. J.; Stuart, L. W.; Hurley, K. P.; Lewis, M. C.; Winegar, D. A.; Wilson, J. G.; Wilkison, W. O.; Ittoop, O. R.; Willson, T. M. Identification of a Subtype Selective Human PPARα Agonist through Parallel-Array Synthesis. Bioorg. Med. Chem. Lett. 2001, 11 (9), 1225– 1227, DOI: 10.1016/S0960-894X(01)00188-3[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjt1Witbo%253D&md5=8cddeedf8db5ade83ebe8e43ad5f6242Identification of a subtype selective human PPARα agonist through parallel-array synthesisBrown, P. J.; Stuart, L. W.; Hurley, K. P.; Lewis, M. C.; Winegar, D. A.; Wilson, J. G.; Wilkison, W. O.; Ittoop, O. R.; Willson, T. M.Bioorganic & Medicinal Chemistry Letters (2001), 11 (9), 1225-1227CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Using solid-phase, parallel-array synthesis, a series of urea-substituted thioisobutyric acids was synthesized and assayed for activity on the human PPAR subtypes. GW7647 (3) was identified as a potent human PPARα agonist with ∼200-fold selectivity over PPARγ and PPARδ, and potent lipid-lowering activity in animal models of dyslipidemia. GW7647 (3) will be a valuable chem. tool for studying the biol. of PPARα in human cells and animal models of disease. Using solid-phase, parallel-array synthesis, a series of urea-substituted thioisobutyric acids was synthesized. GW7647 (3) was identified as a potent, selective human PPARα agonist.
- 113Kane, C. D.; Stevens, K. A.; Fischer, J. E.; Haghpassand, M.; Royer, L. J.; Aldinger, C.; Landschulz, K. T.; Zagouras, P.; Bagley, S. W.; Hada, W.; Dullea, R.; Hayward, C. M.; Francone, O. L. Molecular Characterization of Novel and Selective Peroxisome Proliferator-Activated Receptor α Agonists with Robust Hypolipidemic Activity in Vivo. Mol. Pharmacol. 2009, 75 (2), 296– 306, DOI: 10.1124/mol.108.051656[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlGitr8%253D&md5=e35229c6ec18556e39fb3b2014ca6fa1Molecular characterization of novel and selective peroxisome proliferator-activated receptor α agonists with robust hypolipidemic activity in vivoKane, Christopher D.; Stevens, Kimberly A.; Fischer, James E.; Haghpassand, Mehrdad; Royer, Lori J.; Aldinger, Charles; Landschulz, Katherine T.; Zagouras, Panayiotis; Bagley, Scott W.; Hada, William; Dullea, Robert; Hayward, Cheryl M.; Francone, Omar L.Molecular Pharmacology (2009), 75 (2), 296-306CODEN: MOPMA3; ISSN:0026-895X. (American Society for Pharmacology and Experimental Therapeutics)The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARα agonists with therapeutic potential for treating dyslipidemia. These structurally related compds. display potent and selective binding to human PPARα and support robust recruitment of coactivator peptides in vitro. These compds. markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARα agonists were assessed by transcriptional profiling of mouse liver after short- and long-term treatment. The induction of several known PPARα target genes involved with fatty acid metab. were obsd., reflecting the expected pharmacol. assocd. with PPARα activation. We also noted the down-regulation of a no. of genes related to immune cell function, the acute phase response, and glucose metab., suggesting that these compds. may have anti-inflammatory action in the mammalian liver. Whereas these compds. are efficacious in acute preclin. models, extended safety studies and further clin. testing will be required before the full therapeutic promise of a selective PPARα agonist is realized.
- 114Kuwabara, K.; Murakami, K.; Todo, M.; Aoki, T.; Asaki, T.; Murai, M.; Yano, J. A Novel Selective Peroxisome Proliferator-Activated Receptor α Agonist, 2-Methyl-c-5-[4-[5-Methyl-2-(4-Methylphenyl)-4-Oxazolyl]Butyl]-1, 3-Dioxane-r-2-Carboxylic Acid (NS-220), Potently Decreases Plasma Triglyceride and Glucose Levels and Modifies Lipopr. J. Pharmacol. Exp. Ther. 2004, 309 (3), 970– 977, DOI: 10.1124/jpet.103.064659[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXksFCnsbg%253D&md5=d715ea8cfa76202e3f759fef97038c71A novel selective peroxisome proliferator-activated receptor α agonist, 2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), potently decreases plasma triglyceride and glucose levels and modifies lipoprotein profiles in KK-Ay miceKuwabara, Kenji; Murakami, Kohji; Todo, Makoto; Aoki, Tomiyoshi; Asaki, Tetsuo; Murai, Masatoshi; Yano, JunichiJournal of Pharmacology and Experimental Therapeutics (2004), 309 (3), 970-977CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)NS-220 was newly synthesized and demonstrated to be a novel potent peroxisome proliferator-activated receptor α (PPARα) agonist with high subtype selectivity. In cell-based reporter gene assays, the EC50 values of NS-220 for human PPARα, PPARγ, and PPARδ were 1.9×10-8, 9.6×10-6, and >10-4 M, resp., and for mouse PPARα, PPARγ, and PPARδ were 5.5×10-8, 3.3×10-5, and >10-4 M, resp. In addn., [3H]NS-220 bound to the ligand-binding domain of human PPARα with a KD value of 1.85×10-7 M. Fenofibric acid and bezafibrate showed weak agonist activity for PPARα (EC50, 2-8×10-5 M), with poor subtype selectivity. NS-220 (0.1-3 mg/kg p.o.) decreased plasma triglyceride levels in ddY mice in a dose-dependent manner, but its hypolipidemic activity was abolished in PPARα-deficient mice. In KK-Ay mice, an animal model of type-2 diabetes, NS-220 (0.3-1 mg/kg p.o.; 4 days) and fenofibrate (100-300 mg/kg p.o.; 4 days) decreased plasma triglyceride and glucose levels in a dose-dependent manner. In a 2-wk repeated administration test, NS-220 (0.3-1 mg/kg p.o.) decreased plasma glucose levels markedly without increasing in plasma insulin levels. Furthermore, NS-220 increased high-d. lipoprotein levels and decreased triglyceride-rich lipoprotein levels. In conclusion, a newly synthesized dioxanecarboxylic acid deriv., NS-220, is a potent and highly selective PPARα agonist that ameliorates metabolic disorders in diabetic mice. These results strongly suggest that it will be a promising drug for the treatment of hyperlipidemia or metabolic disorders in type-2 diabetes.
- 115Santilli, A. A.; Scotese, A. C.; Tomarelli, R. M. A Potent Antihypercholesterolemic Agent: [4-Chloro-6-(2,3-Xylidino)-2-Pyrimidinylthio]Acetic Acid (Wy-14643). Experientia 1974, 30 (10), 1110– 1111, DOI: 10.1007/BF01923636[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXmvVaqug%253D%253D&md5=f10efeb39397486a1b850abd711e7748Potent antihypercholesterolemic agent, [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14643)Santilli, A. A.; Scotese, A. C.; Tomarelli, R. M.Experientia (1974), 30 (10), 1110-11CODEN: EXPEAM; ISSN:0014-4754.Wy 14643 (I) [50892-23-4] (0.1-50 mg/day) lowered the blood serum cholesterol levels of rats with dietary hypercholesterolemia in a dose-related manner. I was more potent than clofibrate [637-07-0]. I was prepd. by alkylation of sodium 2-thiobarbiturate [31645-12-2] with ethyl bromoacetate [105-36-2], followed by chlorination and reaction of the resultant product with 2,3-dimethylaniline [87-59-2].
- 116Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. The PPARs: From Orphan Receptors to Drug Discovery. J. Med. Chem. 2000, 43, 527– 550, DOI: 10.1021/jm990554g[ACS Full Text], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXht1Churk%253D&md5=003b19fe3fdf813411d6a2ac5aefdc01The PPARs: From orphan receptors to drug discoveryWillson, Timothy M.; Brown, Peter J.; Sternbach, Daniel D.; Henke, Brad R.Journal of Medicinal Chemistry (2000), 43 (4), 527-550CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review with 326 refs. is given on peroxisome proliferator-activated receptors (PPARs). The structural and functional anal. of the different PPAR subtypes is summarized and their function as hormone receptors for dietary fatty acids and certain eicosanoids in different species and in many metabolically active tissues is described. Progress is reported in the development of drugs, which use PPARs as mol. targets, for the treatment of human metabolic diseases.
- 117Pollinger, J.; Gellrich, L.; Schierle, S.; Kilu, W.; Schmidt, J.; Kalinowsky, L.; Ohrndorf, J.; Kaiser, A.; Heering, J.; Proschak, E.; Merk, D. Tuning Nuclear Receptor Selectivity of Wy14,643 towards Selective Retinoid X Receptor Modulation. J. Med. Chem. 2019, 62 (4), 2112– 2126, DOI: 10.1021/acs.jmedchem.8b01848[ACS Full Text], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlCgs78%253D&md5=627619c57f03ff4d0223c791154a9cffTuning nuclear receptor selectivity of Wy14,643 towards selective retinoid X receptor modulationPollinger, Julius; Gellrich, Leonie; Schierle, Simone; Kilu, Whitney; Schmidt, Jurema; Kalinowsky, Lena; Ohrndorf, Julia; Kaiser, Astrid; Heering, Jan; Proschak, Ewgenij; Merk, DanielJournal of Medicinal Chemistry (2019), 62 (4), 2112-2126CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 (I) in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compd. as an RXR agonist explaining the pleiotropic effects and report its systematic structure-activity relationship anal. with the discovery of specific mol. determinants driving activity on PPARs and RXRs. We have designed close analogs of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacol. tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist (II) revealed activity in vivo and active concns. in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery.
- 118Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.; Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.; Kliewer, S. A.; Lehmann, J. M. The Structure-Activity Relationship between Peroxisome Proliferator-Activated Receptor γ Agonism and the Antihyperglycemic Activity of Thiazolidinediones. J. Med. Chem. 1996, 39 (3), 665– 668, DOI: 10.1021/jm950395a[ACS Full Text], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xjt1Ortw%253D%253D&md5=cc73c6a8157b6ea258b2f6b3deb6c817The Structure-Activity Relationship between Peroxisome Proliferator-Activated Receptor γ Agonism and the Anti-Hyperglycemic Activity of ThiazolidinedionesWillson, Timothy M.; Cobb, Jeffrey E.; Cowan, David J.; Wiethe, Robert W.; Correa, Itzela D.; Prakash, Shimoga R.; Beck, Kelli D.; Moore, Linda B.; Kliewer, Steven A.; Lehmann, Juergen M.Journal of Medicinal Chemistry (1996), 39 (3), 665-8CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of thiazolidinediones and related compds. with known antidiabetic activity were tested for their in vitro activity on the peroxisome proliferator-activated receptor γ (PPARγ). A correlation between the PPARγ agonist activity and the in vivo antihyperglycemic potency in ob/ob mice was obsd. These results suggest that PPARγ is the mol. target for the antidiabetic activity of the thiazolidinediones.
- 119Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A. An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-Activated Receptor γ (PPARγ). J. Biol. Chem. 1995, 270 (22), 12953– 12956, DOI: 10.1074/jbc.270.22.12953[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmtV2itr0%253D&md5=c32a81ccaaa72abfb879238802640b4dAn antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ)Lehmann, Juergen M.; Moore, Linda B.; Simth-Oliver, Tracey A.; Wilkison, William O.; Willson, Timothy M.; Kliewer, Steven A.Journal of Biological Chemistry (1995), 270 (22), 12953-6CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Thiazolidinedione derivs. are antidiabetic agents that increase the insulin sensitivity of target tissues in animal models of non-insulin-dependent diabetes mellitus. In vitro, thiazolidinediones promote adipocyte differentiation of preadipocyte and mesenchymal stem cell lines; however, the mol. basis for this adipogenic effect has remained unclear. Here, the authors report that thiazolidinediones are potent and selective activators of peroxisome proliferator-activated receptor γ(PPARγ), a member of the nuclear receptor superfamily recently shown to function in adipogenesis. The most potent of these agents, BRL49653, binds to PPARγ with a Kd of approx. 40 nM. Treatment of pluripotent C3H10T1/2 stem cells with BRL49653 results in efficient differentiation to adipocytes. These data are the first demonstration of a high affinity PPAR ligand and provide strong evidence that PPARγ is a mol. target for the adipogenic effects of thiazolidinediones. Furthermore, these data raise the intriguing possibility that PPARγ is a target for the therapeutic actions of this class of compds.
- 120Brown, K. K.; Henke, B. R.; Blanchard, S. G.; Cobb, J. E.; Mook, R.; Kaldor, I.; Kliewer, S. A.; Lehmann, J. M.; Lenhard, J. M.; Harrington, W. W.; Novak, P. J.; Faison, W.; Binz, J. G.; Hashim, M. A.; Oliver, W. O.; Brown, H. R.; Parks, D. J.; Plunket, K. D.; Tong, W. Q.; Menius, J. A.; Adkison, K.; Noble, S. A.; Willson, T. M. A Novel N-Aryl Tyrosine Activator of Peroxisome Proliferator-Activated Receptor-γ Reverses the Diabetic Phenotype of the Zucker Diabetic Fatty Rat. Diabetes 1999, 48 (7), 1415– 1424, DOI: 10.2337/diabetes.48.7.1415[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXktFantbc%253D&md5=2a9d1c260d352ba195efbc6006a30b2bA novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-γ reverses the diabetic phenotype of the Zucker diabetic fatty ratBrown, Kathleen K.; Henke, Brad R.; Blanchard, Steven G.; Cobb, Jeff E.; Mook, Robert; Kaldor, Istvan; Kliewer, Steven A.; Lehmann, Jurgen M.; Lenhard, James M.; Harrington, Wallace W.; Novak, Paul J.; Faison, Walter; Binz, Jane G.; Hashim, Mir A.; Oliver, William O.; Brown, H. Roger; Parks, Derek J.; Plunket, Kelli D.; Tong, Wei-Qin; Menius, J. Alan; Adkison, Kimberly; Noble, Stewart A.; Willson, Timothy M.Diabetes (1999), 48 (7), 1415-1424CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association)The discovery that peroxisome proliferator-activated receptor (PPAR)-γ was the mol. target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-γ in the regulation of carbohydrate and lipid metab. Through the use of high-through-put biochem. assays, GW1929, a novel N-aryl tyrosine activator of human PPAR-γ, was identified. Chronic oral administration of GW1929 or troglitazone to Zucker diabetic fatty (ZDF) rats resulted in dose-dependent decreases in daily glucose, free fatty acid, and triglyceride exposure compared with pretreatment values, as well as significant decreases in glycosylated Hb. Whole body insulin sensitivity, as detd. by the euglycemic-hyperinsulinemic clamp technique, was significantly increased in treated animals. Comparison of the magnitude of glucose lowering as a function of serum drug concns. showed that GW1929 was 2 orders of magnitude more potent than troglitazone in vivo. These data were consistent with the relative in vitro potencies of GW1929 and troglitazone. Isolated perfused pancreas studies performed at the end of the study confirmed that pancreata from vehicle-treated rats showed no increase in insulin secretion in response to a step change in glucose from 3 to 10 mmol/l. In contrast, pancreata from animals treated with GW1929 showed a first- and second-phase insulin secretion pattern. Consistent with the functional data from the perfusion expts., animals treated with the PPAR-γ agonist had more normal islet architecture with preserved insulin staining compared with vehicle-treated ZDF rats. This is the first demonstration of in vivo efficacy of a novel nonthiazolidine-dione identified as a high-affinity ligand for human PPAR-γ. The increased potency of GW1929 compared with troglitazone both in vitro and in vivo may translate into improved clin. efficacy when used as monotherapy in type 2 diabetic patients. In addn., the significant improvement in daily meal tolerance may impact cardiovascular risk factor management in these patients.
- 121Hanke, T.; Cheung, S.-Y.; Kilu, W.; Heering, J.; Ni, X.; Planz, V.; Schierle, S.; Faudone, G.; Friedrich, M.; Wanior, M.; Werz, O.; Windbergs, M.; Proschak, E.; Schubert-Zsilavecz, M.; Chaikuad, A.; Knapp, S.; Merk, D. A Selective Modulator of Peroxisome Proliferator-Activated Receptor γ with an Unprecedented Binding Mode. J. Med. Chem. 2020, 63 (9), 4555– 4561, DOI: 10.1021/acs.jmedchem.9b01786[ACS Full Text], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsl2is7g%253D&md5=7cab05991f3a96acd2c68d3d960685e3A Selective Modulator of Peroxisome Proliferator-Activated Receptor γ with an Unprecedented Binding ModeHanke, Thomas; Cheung, Sun-Yee; Kilu, Whitney; Heering, Jan; Ni, Xiaomin; Planz, Viktoria; Schierle, Simone; Faudone, Giuseppe; Friedrich, Marius; Wanior, Marek; Werz, Oliver; Windbergs, Maike; Proschak, Ewgenij; Schubert-Zsilavecz, Manfred; Chaikuad, Apirat; Knapp, Stefan; Merk, DanielJournal of Medicinal Chemistry (2020), 63 (9), 4555-4561CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The nuclear peroxisome proliferator-activated receptor γ has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also assocd. with marked adverse effects and novel modes of PPARγ modulation are required. Here, we report the discovery and profiling of a new PPARγ modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARγ ligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPARγ activation with a high eudysmic ratio. The new PPARγ modulator revealed outstanding selectivity over the PPARα and PPARδ subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.
- 122Leesnitzer, L. M.; Parks, D. J.; Bledsoe, R. K.; Cobb, J. E.; Collins, J. L.; Consler, T. G.; Davis, R. G.; Hull-Ryde, E. A.; Lenhard, J. M.; Patel, L.; Plunket, K. D.; Shenk, J. L.; Stimmel, J. B.; Therapontos, C.; Willson, T. M.; Blanchard, S. G. Functional Consequences of Cysteine Modification in the Ligand Binding Sites of Peroxisome Proliferator Activated Receptors by GW9662. Biochemistry 2002, 41 (21), 6640– 6650, DOI: 10.1021/bi0159581[ACS Full Text], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtF2htLo%253D&md5=4c8b3355a3a3b43577749d7805f85affFunctional Consequences of Cysteine Modification in the Ligand Binding Sites of Peroxisome Proliferator Activated Receptors by GW9662Leesnitzer, Lisa M.; Parks, Derek J.; Bledsoe, Randy K.; Cobb, Jeff E.; Collins, Jon L.; Consler, Thomas G.; Davis, Roderick G.; Hull-Ryde, Emily A.; Lenhard, James M.; Patel, Lisa; Plunket, Kelli D.; Shenk, Jennifer L.; Stimmel, Julie B.; Therapontos, Christina; Willson, Timothy M.; Blanchard, Steven G.Biochemistry (2002), 41 (21), 6640-6650CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)In the course of a high throughput screen to search for ligands of peroxisome proliferator activated receptor-γ (PPARγ), the authors identified GW9662 using a competition binding assay against the human ligand binding domain. GW9662 had nanomolar IC50 vs. PPARγ and was 10- and 600-fold less potent in binding expts. using PPARα and PPARδ, resp. Pretreatment of all three PPARs with GW9662 resulted in the irreversible loss of ligand binding as assessed by scintillation proximity assay. Incubation of PPAR with GW9662 resulted in a change in the absorbance spectra of the receptors consistent with covalent modification. Mass spectrometric anal. of the PPARγ ligand binding domain treated with GW9662 established Cys285 as the site of covalent modification. This cysteine is conserved among all three PPARs. In cell-based reporter assays, GW9662 was a potent and selective antagonist of full-length PPARγ. The functional activity of GW9662 as an antagonist of PPARγ was confirmed in an assay of adipocyte differentiation. GW9662 showed essentially no effect on transcription when tested using both full-length PPARδ and PPARα. Time-resolved fluorescence assays of ligand-modulated receptor heterodimerization, coactivator binding, and corepressor binding were consistent with the effects obsd. in the reporter gene assays. Control activators increased PPAR: RXR heterodimer formation and coactivator binding to both PPARγ and PPARδ. Corepressor binding was decreased. In the case of PPARα, GW9662 treatment did not significantly increase heterodimerization and coactivator binding or decrease corepressor binding. The exptl. data indicate that GW9662 modification of each of the three PPARs results in different functional consequences. The selective and irreversible nature of GW9662 treatment, and the observation that activity is maintained in cell culture expts., suggests that this compd. may be a useful tool for elucidation of the role of PPARγ in biol. processes.
- 123Oliver, W. R.; Shenk, J. L.; Snaith, M. R.; Russell, C. S.; Plunket, K. D.; Bodkin, N. L.; Lewis, M. C.; Winegar, D. A.; Sznaidman, M. L.; Lambert, M. H.; Xu, H. E.; Sternbach, D. D.; Kliewer, S. A.; Hansen, B. C.; Willson, T. M. A Selective Peroxisome Proliferator-Activated Receptor δ Agonist Promotes Reverse Cholesterol Transport. Proc. Natl. Acad. Sci. U. S. A. 2001, 98 (9), 5306– 5311, DOI: 10.1073/pnas.091021198[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjt1Ontro%253D&md5=a831ae5815399dad336dd50e852ed3f8A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transportOliver, William R., Jr.; Shenk, Jennifer L.; Snaith, Mike R.; Russell, Caroline S.; Plunket, Kelli D.; Bodkin, Noni L.; Lewis, Michael C.; Winegar, Deborah A.; Sznaidman, Marcos L.; Lambert, Millard H.; Xu, H. Eric; Sternbach, Daniel D.; Kliewer, Steven A.; Hansen, Barbara C.; Willson, Timothy M.Proceedings of the National Academy of Sciences of the United States of America (2001), 98 (9), 5306-5311CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metab. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the α (NR1C1) and γ (NR1C3) subtypes, resp. By contrast, the therapeutic potential of the δ (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chem. and structure-based drug design to develop a potent and subtype-selective PPARδ agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high d. lipoprotein cholesterol while lowering the levels of small-dense low d. lipoprotein, fasting triglycerides, and fasting insulin. Our results suggest that PPARδ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease assocd. with the metabolic syndrome X.
- 124Sznaidman, M. L.; Haffner, C. D.; Maloney, P. R.; Fivush, A.; Chao, E.; Goreham, D.; Sierra, M. L.; LeGrumelec, C.; Xu, H. E.; Montana, V. G.; Lambert, M. H.; Willson, T. M.; Oliver, W. R.; Sternbach, D. D. Novel Selective Small Molecule Agonists for Peroxisome Proliferator-Activated Receptor δ (PPARδ) - Synthesis and Biological Activity. Bioorg. Med. Chem. Lett. 2003, 13 (9), 1517– 1521, DOI: 10.1016/S0960-894X(03)00207-5[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXivFemu70%253D&md5=9d0d967f6652b200ba3610657b7676b7Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ) - synthesis and biological activitySznaidman, Marcos L.; Haffner, Curt D.; Maloney, Patrick R.; Fivush, Adam; Chao, Esther; Goreham, Donna; Sierra, Michael L.; LeGrumelec, Christelle; Xu, H. Eric; Montana, Valerie G.; Lambert, Millard H.; Willson, Timothy M.; Oliver, William R.; Sternbach, Daniel D.Bioorganic & Medicinal Chemistry Letters (2003), 13 (9), 1517-1521CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)The authors report the synthesis and biol. activity of a new series of small mol. agonists of the human Peroxisome Proliferator-Activated Receptor δ (PPARδ). Several hits were identified from original libraries contg. lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to two compds. (GW501516 and GW0742) which show an EC50 of 1.1 nM against PPARδ with 1000-fold selectivity over the other human subtypes.
- 125Zhang, R.; Wang, A.; DeAngelis, A.; Pelton, P.; Xu, J.; Zhu, P.; Zhou, L.; Demarest, K.; Murray, W. V.; Kuo, G.-H. Discovery of Para-Alkylthiophenoxyacetic Acids as a Novel Series of Potent and Selective PPARδ Agonists. Bioorg. Med. Chem. Lett. 2007, 17 (14), 3855– 3859, DOI: 10.1016/j.bmcl.2007.05.007[Crossref], [PubMed], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmvVCltbw%253D&md5=b7974387d421bb4f1fa6882ab89733dfDiscovery of para-alkylthiophenoxyacetic acids as a novel series of potent and selective PPARδ agonistsZhang, Rui; Wang, Aihua; DeAngelis, Alan; Pelton, Patricia; Xu, Jun; Zhu, Peifang; Zhou, Lubing; Demarest, Keith; Murray, William V.; Kuo, Gee-HongBioorganic & Medicinal Chemistry Letters (2007), 17 (14), 3855-3859CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)A novel series of potent and selective PPARδ agonists, p-alkylthiophenoxyacetic acids [I, X = S, O, S(O); Y = O, CH2; R = OH, MeO, OMOM, Me, etc.] was identified. The synthesis and structure-activity relationships are described.
- 126Chang, K. L.; Pee, H. N.; Yang, S.; Ho, P. C. Influence of Drug Transporters and Stereoselectivity on the Brain Penetration of Pioglitazone as a Potential Medicine against Alzheimer’s Disease. Sci. Rep. 2015, 5, 9000, DOI: 10.1038/srep09000[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosVKmtb4%253D&md5=9cfe2009ffcd0aa4bea3c887d8dcada5Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer's diseaseChang, Kai Lun; Pee, Hai Ning; Yang, Shili; Ho, Paul C.Scientific Reports (2015), 5 (), 9000CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Pioglitazone is currently undergoing clin. trials for treatment of Alzheimer's disease (AD). However, poor brain penetration remains an obstacle to development of the drug for such intended clin. uses. In this study, we demonstrate that the inhibition of P-glycoprotein (P-gp) significantly increases brain penetration of pioglitazone, whereas inhibition of breast cancer resistance protein (BCRP) has little effect. We also investigate the stereoselectivity of pioglitazone uptake in the brain. When mice were dosed with racemic pioglitazone, the concn. of (+)-pioglitazone was 46.6% higher than that of (-)-pioglitazone in brain tissue and 67.7% lower than that of (-)-pioglitazone in plasma. Dosing mice with pure (+)-pioglitazone led to a 76% increase in brain exposure levels compared to those from an equiv. dose of racemic pioglitazone. Pure (+)-pioglitazone was also shown to have comparable amyloid-lowering capabilities to the racemic pioglitazone in an in vitro AD model. These results suggest that P-gp may act as a stereoselective barrier to prevent pioglitazone entry into the brain. Dosing with (+)-pioglitazone instead of the racemic mixt. may result in higher levels of brain exposure to pioglitazone, thus potentially improving the development of pioglitazone treatment of AD.
- 127Sime, M.; Allan, A. C.; Chapman, P.; Fieldhouse, C.; Giblin, G. M. P.; Healy, M. P.; Lambert, M. H.; Leesnitzer, L. M.; Lewis, A.; Merrihew, R. V.; Rutter, R. A.; Sasse, R.; Shearer, B. G.; Willson, T. M.; Xu, R. X.; Virley, D. J. Discovery of GSK1997132B a Novel Centrally Penetrant Benzimidazole PPARγ Partial Agonist. Bioorg. Med. Chem. Lett. 2011, 21 (18), 5568– 5572, DOI: 10.1016/j.bmcl.2011.06.088[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVKisL3M&md5=7f93f4621adf179a2ff97a2be9849bbbDiscovery of GSK1997132B a novel centrally penetrant benzimidazole PPARγ partial agonistSime, Mairi; Allan, Amanda C.; Chapman, Paul; Fieldhouse, Charlotte; Giblin, Gerard M. P.; Healy, Mark P.; Lambert, Millard H.; Leesnitzer, Lisa M.; Lewis, Ann; Merrihew, Raymond V.; Rutter, Richard A.; Sasse, Rosemary; Shearer, Barry G.; Willson, Timothy M.; Xu, Robert X.; Virley, David J.Bioorganic & Medicinal Chemistry Letters (2011), 21 (18), 5568-5572CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metab., glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B (I) a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.
- 128Uriz-Huarte, A.; Date, A.; Ang, H.; Ali, S.; Brady, H. J. M.; Fuchter, M. J. The Transcriptional Repressor REV-ERB as a Novel Target for Disease. Bioorg. Med. Chem. Lett. 2020, 30 (17), 127395, DOI: 10.1016/j.bmcl.2020.127395[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVWhs7fP&md5=bba3790573dd756a54af723c25224adeThe transcriptional repressor REV-ERB as a novel target for diseaseUriz-Huarte, Amaia; Date, Amrita; Ang, Heather; Ali, Simak; Brady, Hugh J. M.; Fuchter, Matthew J.Bioorganic & Medicinal Chemistry Letters (2020), 30 (17), 127395CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. REV-ERB is a member of the nuclear receptor superfamily of transcription factors involved in the regulation of many physiol. processes, from circadian rhythm, to immune function and metab. Accordingly, REV-ERB has been considered as a promising, but difficult drug target for the treatment of numerous diseases. Here, we concisely review current understanding of the function of REV-ERB, modulation by endogenous factors and synthetic ligands, and the involvement of REV-ERB in select human diseases. Particular focus is placed on the medicinal chem. of synthetic REV-ERB ligands, which demonstrates the need for higher quality ligands to aid in robust validation of this exciting target.
- 129Kojetin, D. J.; Burris, T. P. REV-ERB and ROR Nuclear Receptors as Drug Targets. Nat. Rev. Drug Discovery 2014, 13 (3), 197– 216, DOI: 10.1038/nrd4100[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjt12hsL0%253D&md5=156f56d5766fec38440a3c0f2e9c753eREV-ERB and ROR nuclear receptors as drug targetsKojetin, Douglas J.; Burris, Thomas P.Nature Reviews Drug Discovery (2014), 13 (3), 197-216CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. The nuclear receptors REV-ERB (consisting of REV-ERBα and REV-ERBβ) and retinoic acid receptor-related orphan receptors (RORs; consisting of RORα, RORβ and RORγ) are involved in many physiol. processes, including regulation of metab., development and immunity as well as the circadian rhythm. The recent characterization of endogenous ligands for these former orphan nuclear receptors has stimulated the development of synthetic ligands and opened up the possibility of targeting these receptors to treat several diseases, including diabetes, atherosclerosis, autoimmunity and cancer. This Review focuses on the latest developments in ROR and REV-ERB pharmacol. indicating that these nuclear receptors are druggable targets and that ligands targeting these receptors may be useful in the treatment of several disorders.
- 130Chang, C.; Loo, C.-S.; Zhao, X.; Solt, L. A.; Liang, Y.; Bapat, S. P.; Cho, H.; Kamenecka, T. M.; Leblanc, M.; Atkins, A. R.; Yu, R. T.; Downes, M.; Burris, T. P.; Evans, R. M.; Zheng, Y. The Nuclear Receptor REV-ERBα Modulates Th17 Cell-Mediated Autoimmune Disease. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (37), 18528– 18536, DOI: 10.1073/pnas.1907563116[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslOhsbnF&md5=1409f2e46939feeb39805270b5312545The nuclear receptor REV-ERBα modulates Th17 cell-mediated autoimmune diseaseChang, Christina; Loo, Chin-San; Zhao, Xuan; Solt, Laura A.; Liang, Yuqiong; Bapat, Sagar P.; Cho, Han; Kamenecka, Theodore M.; Leblanc, Mathias; Atkins, Annette R.; Yu, Ruth T.; Downes, Michael; Burris, Thomas P.; Evans, Ronald M.; Zheng, YeProceedings of the National Academy of Sciences of the United States of America (2019), 116 (37), 18528-18536CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)T helper 17 (Th17) cells produce interleukin-17 (IL-17) cytokines and drive inflammatory responses in autoimmune diseases such as multiple sclerosis. The differentiation of Th17 cells is dependent on the retinoic acid receptor-related orphan nuclear receptor RORγt. Here, we identify REV-ERBα (encoded by Nr1d1), a member of the nuclear hormone receptor family, as a transcriptional repressor that antagonizes RORγt function in Th17 cells. REV-ERBα binds to ROR response elements (RORE) in Th17 cells and inhibits the expression of RORγt-dependent genes including Il17a and Il17f. Furthermore, elevated REV-ERBα expression or treatment with a synthetic REV-ERB agonist significantly delays the onset and impedes the progression of exptl. autoimmune encephalomyelitis (EAE). These results suggest that modulating REV-ERBα activity may be used to manipulate Th17 cells in autoimmune diseases.
- 131Lazar, M. A.; Hodin, R. A.; Darling, D. S.; Chin, W. W. A Novel Member of the Thyroid/Steroid Hormone Receptor Family Is Encoded by the Opposite Strand of the Rat c-ErbA Alpha Transcriptional Unit. Mol. Cell. Biol. 1989, 9 (3), 1128– 1136, DOI: 10.1128/MCB.9.3.1128[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXhs1Wn&md5=41918d675e93b04c84aa4f0288af9232A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbAα transcriptional unitLazar, Mitchell A.; Hodin, Richard A.; Darling, Douglas S.; Chin, William W.Molecular and Cellular Biology (1989), 9 (3), 1128-36CODEN: MCEBD4; ISSN:0270-7306.A cDNA encoding a novel member of the thyroid/steroid hormone receptor superfamily, called Rev-ErbAα, was isolated from a rat GH3 cell library. Rev-ErbAα is an ∼56-kilodalton protein most similar in structure to the thyroid hormone receptor (c-erbA) and the retinoic acid receptor, but it does not bind either thyroid hormone or retinoic acid. The mRNA encoding Rev-ErbAα is present in many tissues and is particularly abundant in skeletal muscle and brown fat. A genomic DNA fragment contg. the entire Rev-ErbAα cDNA sequence was isolated and characterized. Remarkably, this DNA fragment also contained a portion of the c-erbAα gene. The r-erbAα-1 and r-erbAα-2 are alternative splice products of the c-erbAα gene and are members of the receptor superfamily. The genes encoding Rev-ErbAα and r-erbAα-2 overlap, with their coding strands oriented opposite one another. A 269-base-pair segment of the bidirectionally transcribed region is exonic in both the Rev-ErbAα and r-erbAα-2 genes, resulting in complementary mRNAs. Thus, through alternative splicing and opposite-strand transcription, a single genomic locus codes for three different members of the thyroid/steroid hormone receptor superfamily. Potential implications of this unusual genomic arrangement are discussed.
- 132Forman, B. M.; Chen, J.; Blumberg, B.; Kliewer, S. A.; Henshaw, R.; Ong, E. S.; Evans, R. M. Cross-Talk among ROR Alpha 1 and the Rev-Erb Family of Orphan Nuclear Receptors. Mol. Endocrinol. 1994, 8 (9), 1253– 1261, DOI: 10.1210/mend.8.9.7838158[Crossref], [PubMed], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmslemsLo%253D&md5=00c997fe0b6796f17e750611d590632dCross-talk among RORα1 and the Rev-erb family of orphan nuclear receptorsForman, Barry Marc; Chen, Jasmine; Blumberg, Bruce; Kliewer, Steven A.; Henshaw, Robert; Ong, Estelita S.; Evans, Ronald M.Molecular Endocrinology (1994), 8 (9), 1253-61CODEN: MOENEN; ISSN:0888-8809.We have cloned Rev-erbβ, a novel isoform of the Rev-erbα orphan nuclear receptor. The DNA binding domains of Rev-erbα and β are highly related to each other and to the retinoic acid related orphan receptor (ROR)/RZR subfamily of nuclear receptors. Indeed, we find that all three receptors bind as monomers to the sequence AATGT-AGGTCA. Whereas RORαf1 constitutively activates transcription through this sequence, both isoforms of Reverb are inactive. When coexpressed, both Rev-erb isoforms suppress the transcriptional activity of RORα1. Our data define Rev-erb and ROR/RZR as a family of related receptors with opposing activities on overlapping regulatory networks.
- 133Dumas, B.; Harding, H. P.; Choi, H. S.; Lehmann, K. A.; Chung, M.; Lazar, M. A.; Moore, D. D. A New Orphan Member of the Nuclear Hormone Receptor Superfamily Closely Related to Rev-Erb. Mol. Endocrinol. 1994, 8 (8), 996– 1005, DOI: 10.1210/mend.8.8.7997240[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXlslSksbk%253D&md5=d0fcc97317dd13640d2acf7effa67028A new orphan member of the nuclear hormone receptor superfamily closely related to Rev-ErbDumas, Bruno; Harding, Heather P.; Choi, Hueng-Sik; Lehmann, Katrina A.; Chung, Mirra; Lazar, Mitchell A.; Moore, David D.Molecular Endocrinology (1994), 8 (8), 996-1005CODEN: MOENEN; ISSN:0888-8809.We have isolated complementary DNA clones encoding a novel orphan member of the nuclear receptor superfamily, termed BD73. This protein shows strong amino acid sequence similarity to the previously described Rev-ErbAα. Unlike Rev-Erb, in which the opposite strand of the C-terminal coding region encodes the C-terminal portion of a variant thyroid hormone receptor isoform, the opposite strand of the C-terminal coding region of BD73 does not have any extensive open reading frames. BD73 mRNA levels are strongly induced by planar arom. antioxidants. Like Rev-Erb, BD73 binds as a monomer to a DNA sequence which consists of a specific A/T-rich sequence upstream of the consensus hexameric half-site specified by the P box of the DNA-binding domain. Amino acid sequence comparisons suggest that the A box sequence, which has been suggested to mediate monomer binding by other superfamily members, lies closer to the DNA-binding domain in BD73 and Rev-Erb than in other receptors. Under the conditions examd., neither BD73 nor Rev-Erb activated reporters contg. multiple copies of their common binding site. Thus, these two orphans may require an as yet unidentified ligand or other signal for such activation. Together, BD73 and Rev-Erb define a subgroup of orphan receptors that bind as monomers to a half-site flanked by a specific and extended A/T-rich sequence.
- 134Yin, L.; Lazar, M. A. The Orphan Nuclear Receptor Rev-Erbα Recruits the N-CoR/Histone Deacetylase 3 Corepressor to Regulate the Circadian Bmal1 Gene. Mol. Endocrinol. 2005, 19 (6), 1452– 1459, DOI: 10.1210/me.2005-0057[Crossref], [PubMed], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkslyqtro%253D&md5=8a1272733fd5b36d75debb72ba1db1a9The orphan nuclear receptor Rev-erbα recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 geneYin, Lei; Lazar, Mitchell A.Molecular Endocrinology (2005), 19 (6), 1452-1459CODEN: MOENEN; ISSN:0888-8809. (Endocrine Society)Transcriptional regulation plays a fundamental role in controlling circadian oscillation of clock gene expression. The orphan nuclear receptor Rev-erbα has recently been implicated as a major regulator of the circadian clock. Expression of Bmal1, the master regulator of circadian rhythm in mammals, is neg. correlated with Rev-erbα mRNA level, but the mol. mechanism underlying this regulation is largely unknown. Here we show that Rev-erbα dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human. Rev-erbα directly binds to the mouse Bmal1 promoter and recruits the endogenous nuclear receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex, in assocn. with a decrease in histone acetylation. The endogenous N-CoR/HDAC3 complex is also assocd. with the endogenous Bmal1 promoter in human HepG2 liver cells, where a redn. in cellular HDAC3 level markedly increases the expression of Bmal1 mRNA. These data demonstrate a new function for the N-CoR/HDAC3 complex in regulating the expression of genes involved in circadian rhythm by functioning as corepressor for Rev-erbα.
- 135Torra, I. P.; Tsibulsky, V.; Delaunay, F.; Saladin, R.; Laudet, V.; Fruchart, J.-C.; Kosykh, V.; Staels, B. Circadian and Glucocorticoid Regulation of Rev-Erbα Expression in Liver. Endocrinology 2000, 141 (10), 3799– 3806, DOI: 10.1210/endo.141.10.7708[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmvVGmsbc%253D&md5=9554cf7fff2be9ac83718c9c94bd844eCircadian and glucocorticoid regulation of Rev-erbα expression in liverTorra, Ines Pineda; Tsibulsky, Vladimir; Delaunay, Franck; Saladin, Regis; Laudet, Vincent; Fruchart, Jean-Charles; Kosykh, Vladimir; Staels, BartEndocrinology (2000), 141 (10), 3799-3806CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)Rev-erbα [NR1D1], a member of the nuclear receptor superfamily, is an orphan receptor that constitutively represses gene transcription. Rev-erbα has been shown to play a role in myocyte differentiation and to be induced during adipogenesis. Furthermore, Rev-erbα is a regulator of lipoprotein metab. It was recently shown that Rev-erbα mRNA levels oscillate diurnally in rat liver. Here, the authors report that the circadian rhythm of Rev-erbα in liver is maintained in primary cultures of rat hepatocytes. Because glucocorticoids have been shown to regulate other transcription factors with circadian expression, it was furthermore examd. whether hepatic Rev-erbα expression is also regulated by glucocorticoids. Treatment of rats with dexamethasone resulted in a decrease of Rev-erbα mRNA levels by 70% after 6 h. Furthermore, dexamethasone decreased Rev-erbα expression in rat primary hepatocytes in a dose-dependent fashion. This effect was mediated by the glucocorticoid receptor because simultaneous addn. of the glucocorticoid antagonist RU486 prevented the decrease in Rev-erbα mRNA levels by dexamethasone. Protein synthesis inhibition with cycloheximide markedly induced Rev-erbα mRNA levels; however, this induction was reduced by dexamethasone supplementation in both rat and human primary hepatocytes. Treatment with actinomycin D blocked the repression of Rev-erbα expression by dexamethasone in rat hepatocytes, suggesting that glucocorticoids regulate Rev-erbα expression at the transcriptional level. Transient transfection expts. further indicated that Rev-erbα promoter activity is repressed by dexamethasone in the presence of cotransfected glucocorticoid receptor. Taken together, these data demonstrate that Rev-erbα expression is under the control of both the circadian clock and glucocorticoids in the liver.
- 136Balsalobre, A.; Damiola, F.; Schibler, U. A Serum Shock Induces Circadian Gene Expression in Mammalian Tissue Culture Cells. Cell 1998, 93 (6), 929– 937, DOI: 10.1016/S0092-8674(00)81199-X[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjvFKqsL8%253D&md5=989e59d9fb65ffa90a7f2700dcc19804A serum shock induces circadian gene expression in mammalian tissue culture cellsBalsalobre, Aurelio; Damiola, Francesca; Schibler, UeliCell (Cambridge, Massachusetts) (1998), 93 (6), 929-937CODEN: CELLB5; ISSN:0092-8674. (Cell Press)The treatment of cultured rat-1 fibroblasts or H35 hepatoma cells with high concns. of serum induces the circadian expression of various genes whose transcription also oscillates in living animals. Oscillating genes include rper1 and rper2 (rat homologs of the Drosophila clock gene period), and the genes encoding the transcription factors Rev-Erbα, DBP, and TEF. In rat-1 fibroblasts, up to three consecutive daily oscillations with an av. period length of 22.5 h could be recorded. The temporal sequence of the various mRNA accumulation cycles is the same in cultured cells and in vivo. The serum shock of rat-1 fibroblasts also results in a transient stimulation of c-fos and rper expression and thus mimics light-induced immediate-early gene expression in the suprachiasmatic nucleus.
- 137Wolff, S. E. C.; Wang, X.-L.; Jiao, H.; Sun, J.; Kalsbeek, A.; Yi, C.-X.; Gao, Y. The Effect of Rev-Erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia. Front. Immunol. 2020, 11, 550145, DOI: 10.3389/fimmu.2020.550145[Crossref], [PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1aktbrP&md5=d45e74ce639254e0c585dfb59d4bb841The Effect of Rev-erba agonist SR9011 on the immune response and cell metabolism of microgliaWolff, Samantha E. C.; Wang, Xiao-Lan; Jiao, Han; Sun, Jia; Kalsbeek, Andries; Yi, Chun-Xia; Gao, YuanqingFrontiers in Immunology (2020), 11 (), 550145CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)Microglia are the immune cells of the brain. Hyperactivation of microglia contributes to the pathol. of metabolic and neuroinflammatory diseases. Evidence has emerged that links the circadian clock, cellular metab., and immune activity in microglia. Rev-erb nuclear receptors are known for their regulatory role in both the mol. clock and cell metab., and have recently been found to play an important role in neuroinflammation. The Rev-erb αagonist SR9011 disrupts circadian rhythm by altering intracellular clock machinery. However, the exact role of Rev-erb αin microglial immunometabolism remains to be elucidated. In the current study, we explored whether SR9011 also had such a detrimental impact on microglial immunometabolic functions. Primary microglia were isolated from 1-3 days old Sprague-Dawley rat pups. The expression of clock genes, cytokines and metabolic genes was evaluated using RT-PCR and rhythmic expression was analyzed. Phagocytic activity was detd. by the uptake capacity of fluorescent microspheres. Mitochondria function was evaluated by measuring oxygen consumption rate and extracellular acidification rate. We found that key cytokines and metabolic genes are rhythmically expressed in microglia. SR9011 disturbed rhythmic expression of clock genes in microglia. Pro-inflammatory cytokine expression was attenuated by SR9011 during an immune challenge by TNF α, while expression of the anti-inflammatory cytokine Il10 was stimulated. Moreover, SR9011 decreased phagocytic activity, mitochondrial respiration, ATP prodn., and metabolic gene expression. Our study highlights the link between the intrinsic clock and immunometabolism of microglia. We show that Rev-erb α is implicated in both metabolic homeostasis and the inflammatory responses in microglia, which has important implications for the treatment of metabolic and neuroinflammatory diseases.
- 138Guo, D.; Zhu, Y.; Sun, H.; Xu, X.; Zhang, S.; Hao, Z.; Wang, G.; Mu, C.; Ren, H. Pharmacological Activation of REV-ERBα Represses LPS-Induced Microglial Activation through the NF-KB Pathway. Acta Pharmacol. Sin. 2019, 40 (1), 26– 34, DOI: 10.1038/s41401-018-0064-0[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVOnu7nN&md5=7a60e0feb50dbf9bed8d441df67e2c8bPharmacological activation of REV-ERBa represses LPS-induced microglial activation through the NF-kB pathwayGuo, Dong-kai; Zhu, Yao; Sun, Hong-yang; Xu, Xing-yun; Zhang, Shun; Hao, Zong-bing; Wang, Guang-hui; Mu, Chen-chen; Ren, Hai-gangActa Pharmacologica Sinica (2019), 40 (1), 26-34CODEN: APSCG5; ISSN:1671-4083. (Nature Research)Microglia-mediated neuroinflammation is tightly assocd. with various neurodegenerative diseases and psychiatric disorders. However, the role of REV-ERBa in neuroinflammation is largely unclear. In this study, we investigated whether and how pharmacol. activation of REV-ERBa affected lipopolysaccharide (LPS)-induced neuroinflammation in mouse microglia in vitro and in vivo. In BV2 cells or primary mouse cultured microglia, application of REV-ERBa agonist GSK4112 or SR9011 dose-dependently suppressed LPS-induced microglial activation through the nuclear factor kappa B (NF-kB) pathway. In BV2 cells, pretreatment with GSK4112 inhibited LPS-induced phosphorylation of the inhibitor of NF-kB alpha (IkBa) kinase (IkK), thus restraining the phosphorylation and degrdn. of IkBa, and blocked the nuclear translocation of p65, a NF-kB subunit, thereby suppressing the expression and secretion of the proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor a (TNFa). Moreover, REV-ERBa agonist-induced inhibition on neuroinflammation protected neurons from microglial activation-induced damage, which were also demonstrated in mice with their ventral midbrain microinjected with GSK4112, and then stimulated with LPS. Our results reveal that enhanced REV-ERBa activity suppresses microglial activation through the NF-kB pathway in the central nervous system.
- 139Roby, D. A.; Ruiz, F.; Kermath, B. A.; Voorhees, J. R.; Niehoff, M.; Zhang, J.; Morley, J. E.; Musiek, E. S.; Farr, S. A.; Burris, T. P. Pharmacological Activation of the Nuclear Receptor REV-ERB Reverses Cognitive Deficits and Reduces Amyloid-β Burden in a Mouse Model of Alzheimer’s Disease. PLoS One 2019, 14 (4), e0215004, DOI: 10.1371/journal.pone.0215004[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpslWnu7c%253D&md5=6ffeb1c6dd79062fd2e0552b1059cea7Pharmacological activation of the nuclear receptor REV-ERB reverses cognitive deficits and reduces amyloid-β burden in a mouse model of Alzheimer's diseaseRoby, Deborah A.; Ruiz, Fernanda; Kermath, Bailey A.; Voorhees, Jaymie R.; Niehoff, Michael; Zhang, Jinsong; Morley, John E.; Musiek, Erik S.; Farr, Susan A.; Burris, Thomas P.PLoS One (2019), 14 (4), e0215004CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Alzheimer's disease currently lacks treatment options that effectively reverse the biol./anatomical pathol. and cognitive deficits assocd. with the disease. Loss of function of the nuclear receptor REV-ERB is assocd. with reduced cognitive function in mouse models. The effect of enhanced REV-ERB activity on cognitive function has not been examd. In this study, we tested the hypothesis that enhanced REV-ERB function may enhance cognitive function in a model of Alzheimer's disease. We utilized the REV-ERB agonist SR9009 to pharmacol. activate the activity of REV-ERB in the SAMP8 mouse model of Alzheimer's disease. SR9009 reversed cognitive dysfunction of an aged SAMP8 mouse in several behavioral assays including novel object recognition, T-maze foot shock avoidance, and lever press operant conditioning task assessments. SR9009 treatment reduced amyloid-β 1-40 and 1-42 levels in the cortex, which is consistent with improved cognitive function. Furthermore, SR9009 treatment led to increased hippocampal PSD-95, cortical synaptophysin expression and the no. of synapses suggesting improvement in synaptic function. We conclude that REV-ERB is a potential target for treatment of Alzheimer's disease.
- 140Griffin, P.; Dimitry, J. M.; Sheehan, P. W.; Lananna, B. V.; Guo, C.; Robinette, M. L.; Hayes, M. E.; Cedeño, M. R.; Nadarajah, C. J.; Ezerskiy, L. A.; Colonna, M.; Zhang, J.; Bauer, A. Q.; Burris, T. P.; Musiek, E. S. Circadian Clock Protein Rev-Erbα Regulates Neuroinflammation. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (11), 5102– 5107, DOI: 10.1073/pnas.1812405116[Crossref], [PubMed], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkvVCjtbw%253D&md5=abd5ddc720e1bb661f2b932ecbc97a12Circadian clock protein Rev-erbα regulates neuroinflammationGriffin, Percy; Dimitry, Julie M.; Sheehan, Patrick W.; Lananna, Brian V.; Guo, Chun; Robinette, Michelle L.; Hayes, Matthew E.; CedeA±o, Michelle R.; Nadarajah, Collin J.; Ezerskiy, Lubov A.; Colonna, Marco; Zhang, Jinsong; Bauer, Adam Q.; Burris, Thomas P.; Musiek, Erik S.Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (11), 5102-5107CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are assocd. with neuroinflammation. Circadian rhythm dysfunction has been assocd. with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα±, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We obsd. time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα mice. Rev-erbα± deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic anal. of hippocampus from Rev-erbα mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunopptn. revealed that Rev-erbα± phys. interacts with the promoter regions of several NF-κB-related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacol. activation of Rev-erbs with the small mol. agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erb± deletion influenced neuronal health, as conditioned media from Rev-erbα-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that obsd. in neurodegenerative models. Our results reveal Rev-erbα as a pharmacol. accessible link between the circadian clock and neuroinflammation.
- 141Lee, J.; Kim, D. E.; Griffin, P.; Sheehan, P. W.; Kim, D.-H.; Musiek, E. S.; Yoon, S.-Y. Inhibition of REV-ERBs Stimulates Microglial Amyloid-Beta Clearance and Reduces Amyloid Plaque Deposition in the 5XFAD Mouse Model of Alzheimer’s Disease. Aging Cell 2020, 19 (2), e13078, DOI: 10.1111/acel.13078[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1yjtrrN&md5=c318b7b7d2d3efb2a092ae1787bf8de9Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer's diseaseLee, Jiyeon; Kim, Do-Eun; Griffin, Percy; Sheehan, Patrick W.; Kim, Dong-Hou; Musiek, Erik S.; Yoon, Seung-YongAging Cell (2020), 19 (2), e13078CODEN: ACGECQ; ISSN:1474-9718. (Wiley-Blackwell)A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the mol. clock in regulating amyloid-beta (Aβ) pathol. is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ1-42 (fAβ1-42) than at CT12. BMAL1 directly drives transcription of REV-ERB proteins, which are implicated in microglial activation. Interestingly, pharmacol. inhibition of REV-ERBs with the small mol. antagonist SR8278 or genetic knockdown of REV-ERBs-accelerated microglial uptake of fAβ1-42 and increased transcription of BMAL1. SR8278 also promoted microglia polarization toward a phagocytic M2-like phenotype with increased P2Y12 receptor expression. Finally, constitutive deletion of Rev-erba in the 5XFAD model of AD decreased amyloid plaque no. and size and prevented plaque-assocd. increases in disease-assocd. microglia markers including TREM2, CD45, and Clec7a. Altogether, our work suggests a novel strategy for controlling Aβ clearance and neuroinflammation by targeting REV-ERBs and provides new insights into the role of REV-ERBs in AD.
- 142Raghuram, S.; Stayrook, K. R.; Huang, P.; Rogers, P. M.; Nosie, A. K.; McClure, D. B.; Burris, L. L.; Khorasanizadeh, S.; Burris, T. P.; Rastinejad, F. Identification of Heme as the Ligand for the Orphan Nuclear Receptors REV-ERBα and REV-ERBβ. Nat. Struct. Mol. Biol. 2007, 14 (12), 1207– 1213, DOI: 10.1038/nsmb1344[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtl2hu73E&md5=62aabcd486e5edb811d7ea18597ce77aIdentification of heme as the ligand for the orphan nuclear receptors REV-ERBα and REV-ERBβRaghuram, Srilatha; Stayrook, Keith R.; Huang, Pengxiang; Rogers, Pamela M.; Nosie, Amanda K.; McClure, Don B.; Burris, Lorri L.; Khorasanizadeh, Sepideh; Burris, Thomas P.; Rastinejad, FraydoonNature Structural & Molecular Biology (2007), 14 (12), 1207-1213CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)The nuclear receptors REV-ERBα (encoded by NR1D1) and REV-ERBβ (NR1D2) have remained orphans owing to the lack of identified physiol. ligands. Here we show that heme is a physiol. ligand of both receptors. Heme assocs. with the ligand-binding domains of the REV-ERB receptors with a 1:1 stoichiometry and enhances the thermal stability of the proteins. Results from expts. of heme depletion in mammalian cells indicate that heme binding to REV-ERB causes the recruitment of the co-repressor NCoR, leading to repression of target genes including BMAL1 (official symbol ARNTL), an essential component of the circadian oscillator. Heme extends the known types of ligands used by the human nuclear receptor family beyond the endocrine hormones and dietary lipids described so far. Our results further indicate that heme regulation of REV-ERBs may link the control of metab. and the mammalian clock.
- 143Trump, R. P.; Bresciani, S.; Cooper, A. W. J.; Tellam, J. P.; Wojno, J.; Blaikley, J.; Orband-Miller, L. A.; Kashatus, J. A.; Boudjelal, M.; Dawson, H. C.; Loudon, A.; Ray, D.; Grant, D.; Farrow, S. N.; Willson, T. M.; Tomkinson, N. C. O. Optimized Chemical Probes for REV-ERBα. J. Med. Chem. 2013, 56 (11), 4729– 4737, DOI: 10.1021/jm400458q[ACS Full Text], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsVWisr8%253D&md5=cbce9246fa2f76ecfc78bc87d5c40a0fOptimized Chemical Probes for REV-ERBαTrump, Ryan P.; Bresciani, Stefano; Cooper, Anthony W. J.; Tellam, James P.; Wojno, Justyna; Blaikley, John; Orband-Miller, Lisa A.; Kashatus, Jennifer A.; Boudjelal, Mohamed; Dawson, Helen C.; Loudon, Andrew; Ray, David; Grant, Daniel; Farrow, Stuart N.; Willson, Timothy M.; Tomkinson, Nicholas C. O.Journal of Medicinal Chemistry (2013), 56 (11), 4729-4737CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)REV-ERBα has emerged as an important target for regulation of circadian rhythm and its assocd. physiol. Herein, the authors report on the optimization of a series of REV-ERBα agonists based on GSK4112 for potency, selectivity, and bioavailability. Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either i.v. or oral dosing.
- 144Noel, R.; Song, X.; Shin, Y.; Banerjee, S.; Kojetin, D.; Lin, L.; Ruiz, C. H.; Cameron, M. D.; Burris, T. P.; Kamenecka, T. M. Synthesis and SAR of Tetrahydroisoquinolines as Rev-Erbα Agonists. Bioorg. Med. Chem. Lett. 2012, 22 (11), 3739– 3742, DOI: 10.1016/j.bmcl.2012.04.023[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsF2ltb4%253D&md5=87d4951c1b9c2db42a71f0a1522b84d3Synthesis and SAR of tetrahydroisoquinolines as Rev-erbα agonistsNoel, Romain; Song, Xinyi; Shin, Youseung; Banerjee, Subhashis; Kojetin, Douglas; Lin, Li; Ruiz, Claudia H.; Cameron, Michael D.; Burris, Thomas P.; Kamenecka, Theodore M.Bioorganic & Medicinal Chemistry Letters (2012), 22 (11), 3739-3742CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The design and synthesis of a novel series of Rev-erbα agonists is described. The development and optimization of the tetrahydroisoquinoline series was carried out from an earlier acyclic series of Rev-erbα agonists. Through the optimization of the scaffold I, several potent compds. with good in vivo profiles were discovered.
- 145Westermaier, Y.; Ruiz-Carmona, S.; Theret, I.; Perron-Sierra, F.; Poissonnet, G.; Dacquet, C.; Boutin, J. A.; Ducrot, P.; Barril, X. Binding Mode Prediction and MD/MMPBSA-Based Free Energy Ranking for Agonists of REV-ERBα/NCoR. J. Comput.-Aided Mol. Des. 2017, 31 (8), 755– 775, DOI: 10.1007/s10822-017-0040-7[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFOlu73F&md5=0f655bb3cb92851272023caa6e7a93fcBinding mode prediction and MD/MMPBSA-based free energy ranking for agonists of REV-ERBα/NCoRWestermaier, Yvonne; Ruiz-Carmona, Sergio; Theret, Isabelle; Perron-Sierra, Francoise; Poissonnet, Guillaume; Dacquet, Catherine; Boutin, Jean A.; Ducrot, Pierre; Barril, XavierJournal of Computer-Aided Molecular Design (2017), 31 (8), 755-775CODEN: JCADEQ; ISSN:0920-654X. (Springer)The knowledge of the free energy of binding of small mols. to a macromol. target is crucial in drug design as is the ability to predict the functional consequences of binding. We highlight how a mol. dynamics (MD)-based approach can be used to predict the free energy of small mols., and to provide priorities for the synthesis and the validation via in vitro tests. Here, we study the dynamics and energetics of the nuclear receptor REV-ERBα with its co-repressor NCoR and 35 novel agonists. Our in silico approach combines mol. docking, mol. dynamics (MD), solvent-accessible surface area (SASA) and mol. mechanics poisson boltzmann surface area (MMPBSA) calcns. While docking yielded initial hints on the binding modes, their stability was assessed by MD. The SASA calcns. revealed that the presence of the ligand led to a higher exposure of hydrophobic REV-ERB residues for NCoR recruitment. MMPBSA was very successful in ranking ligands by potency in a retrospective and prospective manner. Particularly, the prospective MMPBSA ranking-based validations for four compds., three predicted to be active and one weakly active, were confirmed exptl.
- 146Kojetin, D.; Wang, Y.; Kamenecka, T. M.; Burris, T. P. Identification of SR8278, a Synthetic Antagonist of the Nuclear Heme Receptor REV-ERB. ACS Chem. Biol. 2011, 6 (2), 131– 134, DOI: 10.1021/cb1002575[ACS Full Text], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtl2rs7fI&md5=2de14b79ed592d0062e9e4bc34620892Identification of SR8278, a Synthetic Antagonist of the Nuclear Heme Receptor REV-ERBKojetin, Douglas; Wang, Yongjun; Kamenecka, Theodore M.; Burris, Thomas P.ACS Chemical Biology (2011), 6 (2), 131-134CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)REV-ERBα is a member of the nuclear receptor superfamily that functions as a receptor for the porphoryin heme. REV-ERBα suppresses transcription of its target genes in a heme-dependent manner. Recently, the first nonporphyrin synthetic ligand for REV-ERBα, GSK4112, was designed, and it mimics the action of heme acting as agonist. Here, we report the identification of the first REV-ERB antagonist, SR8278. SR8278 is structurally similar to the agonist but blocks the ability of the GSK4112 to enhance REV-ERBα-dependent repression in a cotransfection assay. Addnl., whereas GSK4112 suppresses the expression of REV-ERBα target genes involved in gluconeogenesis, SR8278 stimulates the expression of these genes. Thus, SR8278 represents a unique chem. tool for probing REV-ERB function and may serve as a point for initiation of further optimization to develop REV-ERB antagonists with the ability to explore circadian and metabolic functions.
- 147De Mei, C; Ercolani, L; Parodi, C; Veronesi, M; Vecchio, C L.; Bottegoni, G; Torrente, E; Scarpelli, R; Marotta, R; Ruffili, R; Mattioli, M; Reggiani, A; Wade, M; Grimaldi, B Dual Inhibition of REV-ERBβ and Autophagy as a Novel Pharmacological Approach to Induce Cytotoxicity in Cancer Cells. Oncogene 2015, 34 (20), 2597– 2608, DOI: 10.1038/onc.2014.203[Crossref], [PubMed], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFGqtr7J&md5=6ae73694ed0eb85a1ab92f28158135e8Dual inhibition of REV-ERBβ and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cellsDe Mei, C.; Ercolani, L.; Parodi, C.; Veronesi, M.; Vecchio, C. Lo; Bottegoni, G.; Torrente, E.; Scarpelli, R.; Marotta, R.; Ruffili, R.; Mattioli, M.; Reggiani, A.; Wade, M.; Grimaldi, B.Oncogene (2015), 34 (20), 2597-2608CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)REV-ERBα and REV-ERBβ nuclear receptors regulate several physiol. processes, including circadian rhythm and metab. A previous study reported the REV-ERBα gene to be co-overexpressed with ERBB2 in breast cancer cell lines. Surprisingly, we found that several tumor types, including a no. of breast cancer cell lines, predominantly express the REV-ERBβ variant. This pattern was independent of ERBB2 and ER status, and opposite to that of non-cancer mammary epithelial HMEC cells, in which REV-ERBα was the major variant. Consistent with this mol. profile, REV-ERB target genes in both circadian and metabolic pathways were derepressed upon silencing of REV-ERBβ, but not REV-ERBα. Strikingly, we found that REV-ERBβ is a determinant of sensitivity to chloroquine, a clin. relevant lysosomotropic agent that suppresses autophagy. The cytoprotective function of REV-ERBβ appears to operate downstream of autophagy blockade. Through compd. screening, we identified ARN5187, a novel lysosomotropic REV-ERBβ ligand with a dual inhibitory activity toward REV-ERB-mediated transcriptional regulation and autophagy. Remarkably, although ARN5187 and chloroquine share similar lysosomotropic potency and have a similar effect on autophagy inhibition, ARN5187 is significantly more cytotoxic. Collectively, our results reveal that dual inhibition of REV-ERBβ and autophagy is an effective strategy for eliciting cytotoxicity in cancer cells. Furthermore, our discovery of a novel inhibitor compd. of both REV-ERB and autophagy may provide a scaffold for the discovery of new multifunctional anticancer agents.
- 148Torrente, E.; Parodi, C.; Ercolani, L.; De Mei, C.; Ferrari, A.; Scarpelli, R.; Grimaldi, B. Synthesis and in Vitro Anticancer Activity of the First Class of Dual Inhibitors of REV-ERBβ and Autophagy. J. Med. Chem. 2015, 58 (15), 5900– 5915, DOI: 10.1021/acs.jmedchem.5b00511[ACS Full Text], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFWgs77I&md5=200ecfe72a200e5b1a944cd9ccac683aSynthesis and in Vitro Anticancer Activity of the First Class of Dual Inhibitors of REV-ERBβ and AutophagyTorrente, Esther; Parodi, Chiara; Ercolani, Luisa; De Mei, Claudia; Ferrari, Alessio; Scarpelli, Rita; Grimaldi, BenedettoJournal of Medicinal Chemistry (2015), 58 (15), 5900-5915CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Autophagy inhibition is emerging as a promising anticancer strategy. We recently reported that the circadian nuclear receptor REV-ERBβ plays an unexpected role in sustaining cancer cell survival when the autophagy flux is compromised. We also identified 4-[[[1-(2-fluorophenyl)cyclopentyl]amino]methyl]-2-[(4-methylpiperazin-1-yl)methyl]phenol, (I; ARN5187), as a novel dual inhibitor of REV-ERBβ and autophagy. I had improved cytotoxicity against BT-474 breast cancer cells compared to chloroquine, a clin. relevant autophagy inhibitor. Here, we present the results of structure-activity studies, based around I, that disclose the first class of dual inhibitors of REV-ERBβ and autophagy. This study led to identification of 1-(4-fluorophenyl)-N-[[3-[(4-methylpiperazin-1-yl)methyl]phenyl]methyl]cyclopentanamine trihydrochloride and 1-(2-fluorophenyl)-N-[[3-[(1-methyl-4-piperidyl)methyl]phenyl]methyl]cyclopentanamide dihydrochloride, which were more effective REV-ERBβ antagonists than I and were more cytotoxic to BT-474. The combination of optimal chem. and structural moieties of these analogs generated II, which elicited 15-fold greater REV-ERBβ inhibitory and cytotoxic activities compared to I. Furthermore, II induced death in a panel of tumor cell lines at doses 5-50 times lower than an equitoxic amt. of chloroquine but did not affect the viability of normal mammary epithelial cells.
- 149Dierickx, P.; Emmett, M. J.; Jiang, C.; Uehara, K.; Liu, M.; Adlanmerini, M.; Lazar, M. A. SR9009 Has REV-ERB–Independent Effects on Cell Proliferation and Metabolism. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (25), 12147– 12152, DOI: 10.1073/pnas.1904226116[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFyktr%252FI&md5=58bd9ff46809fd7f5dbec6fe7b86b4a3SR9009 has REV-ERB-independent effects on cell proliferation and metabolismDierickx, Pieterjan; Emmett, Matthew J.; Jiang, Chunjie; Uehara, Kahealani; Liu, Manlu; Adlanmerini, Marine; Lazar, Mitchell A.Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (25), 12147-12152CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The nuclear receptors REV-ERBα and -β link circadian rhythms and metab. Like other nuclear receptors, REV-ERB activity can be regulated by ligands, including naturally occurring heme. A putative ligand, SR9009, has been reported to elicit a range of beneficial effects in healthy as well as diseased animal models and cell systems. However, the direct involvement of REV-ERBs in these effects of SR9009 has not been thoroughly assessed, as expts. were not performed in the complete absence of both proteins. Here, we report the generation of a mouse model for conditional genetic deletion of REV-ERBα and -β. We show that SR9009 can decrease cell viability, rewire cellular metab., and alter gene transcription in hepatocytes and embryonic stem cells lacking both REV-ERBα and -β. Thus, the effects of SR9009 cannot be used solely as surrogate for REV-ERB activity.
- 150Moore, D. D.; Kato, S.; Xie, W.; Mangelsdorf, D. J.; Schmidt, D. R.; Xiao, R.; Kliewer, S. A. International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor α, Farnesoid X Receptor β, Liver X Receptor α, Liver X Receptor β, and Vitamin D Receptor. Pharmacol. Rev. 2006, 58 (4), 742– 759, DOI: 10.1124/pr.58.4.6[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1aisg%253D%253D&md5=0233111cc7b63bb16aeb179e7a6631e1International union of pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor α, farnesoid X receptor β, liver X receptor α, liver X receptor β, and vitamin D receptorMoore, David D.; Kato, Shigeaki; Xie, Wen; Mangelsdorf, David J.; Schmidt, Daniel R.; Xiao, Rui; Kliewer, Steven A.Pharmacological Reviews (2006), 58 (4), 742-759CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. The nuclear receptors of the NR1H and NR1I subgroups include the constitutive androstane receptor, pregnane X receptor, farnesoid X receptors, liver X receptors, and vitamin D receptor. The newly emerging functions of these related receptors are under the control of metabolic pathways, including metab. of xenobiotics, bile acids, cholesterol, and calcium. This review summarizes results of structural, pharmacol., and genetic studies of these receptors.
- 151Viennois, E.; Mouzat, K.; Dufour, J.; Morel, L.; Lobaccaro, J.-M.; Baron, S. Selective Liver X Receptor Modulators (SLiMs): What Use in Human Health?. Mol. Cell. Endocrinol. 2012, 351 (2), 129– 141, DOI: 10.1016/j.mce.2011.08.036[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtFSht7o%253D&md5=04988d1eea2056d01db65f2c1b49395bSelective liver X receptor modulators (SLiMs): What use in human health?Viennois, Emilie; Mouzat, Kevin; Dufour, Julie; Morel, Laurent; Lobaccaro, Jean-Marc; Baron, SilvereMolecular and Cellular Endocrinology (2012), 351 (2), 129-141CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ireland Ltd.)A review. Liver X receptors (LXR) are members of the nuclear receptor family. As activated transcription factors, their putative assocn. with human diseases makes them promising pharmacol. targets because of the large potential to develop ligands. LXR are mainly considered as intracellular cholesterol "sensors" whose activation leads to decreased plasma cholesterol. They also modulate numerous physiol. functions: fatty acid synthesis and metab., glucose homeostasis, steroidogenesis, immunity, and neurol. homeostasis. LXR-deficiency in mouse results in several phenotypes mimicking pathol. conditions in humans. This review will be focused on the various natural and synthetic LXR agonists and antagonists. Putative clin. targets including atherosclerosis, diabetes, Alzheimer's disease, skin disorders, and cancer will be covered.
- 152Mouzat, K.; Chudinova, A.; Polge, A.; Kantar, J.; Camu, W.; Raoul, C.; Lumbroso, S. Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases?. Int. J. Mol. Sci. 2019, 20 (16), 3858, DOI: 10.3390/ijms20163858[Crossref], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVCgsLY%253D&md5=e06731e71eff008739304a6972bb8f57Regulation of brain cholesterol: what role do liver X receptors play in neurodegenerative diseases?Mouzat, Kevin; Chudinova, Aleksandra; Polge, Anne; Kantar, Jovana; Camu, William; Raoul, Cedric; Lumbroso, SergeInternational Journal of Molecular Sciences (2019), 20 (16), 3858CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concns. and act as transcription factors to promote expression of target genes. Among their numerous physiol. roles, they act as central cholesterollowering factors. In the central nervous system (CNS), cholesterol has been shown to be an essential determinant of brain function, particularly as a major constituent of myelin and membranes. In the brain, LXRs act as cholesterol central regulators, and, beyond this metabolic function, LXRs have addnl. roles such as providing neuroprotective effects and lowering neuroinflammation. In many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis (MS), dysregulations of cholesterol and oxysterol have been reported. In this paper, we propose to focus on recent advances in the knowledge of the LXRs roles on brain cholesterol and oxysterol homeostasis, neuroinflammation, neuroprotection, and their putative involvement in neurodegenerative disorders. We will discuss their potential use as candidates for both mol. diagnosis and as promising pharmacol. targets in the treatment of ALS, AD, or MS patients.
- 153Hong, C.; Tontonoz, P. Liver X Receptors in Lipid Metabolism: Opportunities for Drug Discovery. Nature Reviews Drug Discovery 2014, 13, 433– 444, DOI: 10.1038/nrd4280[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotV2iuro%253D&md5=1d7c39473460b5ecd5ea1c4a3ff18342Liver X receptors in lipid metabolism: opportunities for drug discoveryHong, Cynthia; Tontonoz, PeterNature Reviews Drug Discovery (2014), 13 (6), 433-444CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. The liver X receptors (LXRs) are pivotal regulators of lipid homeostasis in mammals. These transcription factors control the expression of a battery of genes involved in the uptake, transport, efflux and excretion of cholesterol in a tissue-dependent manner. The identification of the LXRs, and an increased understanding of the mechanisms by which LXR signalling regulates lipid homeostasis in different tissues (including the liver, intestine and brain), has highlighted new opportunities for therapeutic intervention in human metab. New strategies for the pharmacol. manipulation of LXRs and their target genes offer promise for the treatment of human diseases in which lipids have a central role, including atherosclerosis and Alzheimer's disease.
- 154Sodhi, R. K.; Singh, N. Liver X Receptors: Emerging Therapeutic Targets for Alzheimer’s Disease. Pharmacol Res. 2013, 72, 45– 51, DOI: 10.1016/j.phrs.2013.03.008[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnt1Sju7s%253D&md5=3dfb6bd42af9b006f95dc7753cd61622Liver X receptors: Emerging therapeutic targets for Alzheimer's diseaseSodhi, Rupinder K.; Singh, NirmalPharmacological Research (2013), 72 (), 45-51CODEN: PHMREP; ISSN:1043-6618. (Elsevier Ltd.)A review. Alzheimer's disease (AD) is a complex neurodegenerative disorder, typified by the pathol. accumulation of ss-amyloid peptides (Ass) and neurofibrillary tangles within the brain, culminating to cognitive impairment. Epidemiol. and biochem. data have suggested a link between cholesterol content, APP (amyloid precursor protein) processing, Ass, inflammation and AD. The intricacy of the disease presents considerable challenges for the development of newer therapeutic agents. Liver X receptors (LXRa and LXRss) are oxysterol activated nuclear receptors that play essential role in lipid and glucose homeostasis, steroidogenesis and inflammatory responses. LXR signalling impacts the development of AD pathol. through multiple pathways. Reports indicate that genetic loss of either lxra or lxrss in APP/PS1 transgenic mice results in increased amyloid plaque load. Studies also suggest that ligand activation of LXRs in Tg2576 mice enhanced, the expression of genes linked with cholesterol efflux e.g. apoe, abca-1, down regulated APP processing and Ass prodn. with significant improvement in memory functions. LXR agonists have also depicted to inhibit neuroinflammation through modulation of microglial phagocytosis and by repressing the expression of cox2, mcp1 and iNos in glial cells. This review summarizes in brief the biol. of LXRs, with an emphasis on their probable pathophysiol. mechanisms that may elicit the defending role of these receptors in brains of AD patients.
- 155Moutinho, M.; Landreth, G. E. Therapeutic Potential of Nuclear Receptor Agonists in Alzheimer’s Disease. J. Lipid Res. 2017, 58 (10), 1937– 1949, DOI: 10.1194/jlr.R075556[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFyltbbM&md5=ea824465a190d51f9c27180915217664Therapeutic potential of nuclear receptor agonists in Alzheimer's diseaseMoutinho, Miguel; Landreth, Gary E.Journal of Lipid Research (2017), 58 (10), 1937-1949CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology)A review. Alzheimer's disease (AD) is characterized by an extensive accumulation of amyloid-β (Aβ) peptide, which triggers a set of deleterious processes, including synaptic dysfunction, inflammation, and neuronal injury, leading to neuronal loss and cognitive impairment. A large body of evidence supports that nuclear receptor (NR) activation could be a promising therapeutic approach for AD. NRs are ligand-activated transcription factors that regulate gene expression and have cell type-specific effects. In this review, we discuss the mechanisms that underlie the beneficial effects of NRs in AD. Moreover, we summarize studies reported in the last 10-15 years and their major outcomes arising from the pharmacol. targeting of NRs in AD animal models. The dissection of the pathways regulated by NRs in the context of AD is of importance in identifying novel and effective therapeutic strategies.
- 156Björkhem, I.; Meaney, S. Brain Cholesterol: Long Secret Life behind a Barrier. Arterioscler., Thromb., Vasc. Biol. 2004, 24 (5), 806– 815, DOI: 10.1161/01.ATV.0000120374.59826.1b[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c3jtlKktw%253D%253D&md5=4273c1fb2054333fdeca963d01ba6fd8Brain cholesterol: long secret life behind a barrierBjorkhem Ingemar; Meaney SteveArteriosclerosis, thrombosis, and vascular biology (2004), 24 (5), 806-15 ISSN:.Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation. Under steady-state conditions, most of the de novo synthesis of cholesterol in the brain appears to be balanced by excretion of the cytochrome P-450-generated oxysterol 24S-hydroxycholesterol. This oxysterol is capable of escaping the recycling mechanism and traversing the blood-brain barrier. Cholesterol levels and cholesterol turnover are affected in neurodegenerating disorders, and the capacity for cholesterol transport and recycling in the brain seems to be of importance for the development of such diseases. The possibility has been discussed that administration of inhibitors of cholesterol synthesis may reduce the prevalence of Alzheimer disease. No firm conclusions can, however, be drawn from the studies presented thus far. In the present review, the most recent advances in our understanding of cholesterol turnover in the brain is discussed.
- 157Hussain, G.; Wang, J.; Rasul, A.; Anwar, H.; Imran, A.; Qasim, M.; Zafar, S.; Kamran, S. K. S.; Razzaq, A.; Aziz, N.; Ahmad, W.; Shabbir, A.; Iqbal, J.; Baig, S. M.; Sun, T. Role of Cholesterol and Sphingolipids in Brain Development and Neurological Diseases. Lipids in Health and Disease 2019, 18, 26, DOI: 10.1186/s12944-019-0965-z[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cjltl2qtQ%253D%253D&md5=1516cf800605ff20baced965dd872729Role of cholesterol and sphingolipids in brain development and neurological diseasesHussain Ghulam; Anwar Haseeb; Zafar Shamaila; Kamran Syed Kashif Shahid; Razzaq Aroona; Aziz Nimra; Ahmad Waseem; Wang Jing; Sun Tao; Rasul Azhar; Imran Ali; Qasim Muhammad; Shabbir Asghar; Iqbal Javed; Baig Shahid MahmoodLipids in health and disease (2019), 18 (1), 26 ISSN:.Brain is a vital organ of the human body which performs very important functions such as analysis, processing, coordination, and execution of electrical signals. For this purpose, it depends on a complex network of nerves which are ensheathed in lipids tailored myelin; an abundant source of lipids in the body. The nervous system is enriched with important classes of lipids; sphingolipids and cholesterol which compose the major portion of the brain particularly in the form of myelin. Both cholesterol and sphingolipids are embedded in the microdomains of membrane rafts and are functional units of the neuronal cell membrane. These molecules serve as the signaling molecules; hold important roles in the neuronal differentiation, synaptogenesis, and many others. Thus, their adequate provision and active metabolism are of crucial importance in the maintenance of physiological functions of brain and body of an individual. In the present review, we have highlighted the physiological roles of cholesterol and sphingolipids in the development of the nervous system as well as the association of their altered metabolism to neurological and neurodegenerative diseases.
- 158Mauch, D. H.; Nägler, K.; Schumacher, S.; Göritz, C.; Müller, E.-C.; Otto, A.; Pfrieger, F. W. CNS Synaptogenesis Promoted by Glia-Derived Cholesterol. Science 2001, 294 (5545), 1354– 1357, DOI: 10.1126/science.294.5545.1354[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXotlKmu7c%253D&md5=106cd66675d04553605f1a1cb57c6e5aCNS synaptogenesis promoted by glia-derived cholesterolMauch, Daniela H.; Naegler, Karl; Schumacher, Stefan; Goertzz, Christian; Mueller, Eva-Christina; Otto, Albrecht; Pfrieger, Frank W.Science (Washington, DC, United States) (2001), 294 (5545), 1354-1357CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The mol. mechanisms controlling synaptogenesis in the central nervous system (CNS) are poorly understood. Previous reports showed that a glia-derived factor strongly promotes synapse development in cultures of purified CNS neurons. Here, we identify this factor as cholesterol complexed to apolipoprotein E-contg. lipoproteins. CNS neurons produce enough cholesterol to survive and grow, but the formation of numerous mature synapses demands addnl. amts. that must be provided by glia. Thus, the availability of cholesterol appears to limit synapse development. This may explain the delayed onset of CNS synaptogenesis after glia differentiation and neurobehavioral manifestations of defects in cholesterol or lipoprotein homeostasis.
- 159Zhang, J.; Liu, Q. Cholesterol Metabolism and Homeostasis in the Brain. Protein Cell 2015, 6 (4), 254– 264, DOI: 10.1007/s13238-014-0131-3[Crossref], [PubMed], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvVent7k%253D&md5=8c80b65527e3c1bbfb12229146588a14Cholesterol metabolism and homeostasis in the brainZhang, Juan; Liu, QiangProtein & Cell (2015), 6 (4), 254-264CODEN: PCREFB; ISSN:1674-800X. (Higher Education Press)Cholesterol is an essential component for neuronal physiol. not only during development stage but also in the adult life. Cholesterol metab. in brain is independent from that in peripheral tissues due to blood-brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metab. has been shown to be implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and some cognitive deficits typical of the old age. The brain contains large amt. of cholesterol, but the cholesterol metab. and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metab. with mol. mechanisms.
- 160Abildayeva, K.; Jansen, P. J.; Hirsch-Reinshagen, V.; Bloks, V. W.; Bakker, A. H. F.; Ramaekers, F. C. S.; De Vente, J.; Groen, A. K.; Wellington, C. L.; Kuipers, F.; Mulder, M. 24(S)-Hydroxycholesterol Participates in a Liver X Receptor-Controlled Pathway in Astrocytes That Regulates Apolipoprotein E-Mediated Cholesterol Efflux. J. Biol. Chem. 2006, 281 (18), 12799– 12808, DOI: 10.1074/jbc.M601019200[Crossref], [PubMed], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjvFKktLs%253D&md5=13dccb379954c2902fd19ce86161ba8824(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol EffluxAbildayeva, Karlygash; Jansen, Paula J.; Hirsch-Reinshagen, Veronica; Bloks, Vincent W.; Bakker, Arjen H. F.; Ramaekers, Frans C. S.; de Vente, Jan; Groen, Albert K.; Wellington, Cheryl L.; Kuipers, Folkert; Mulder, MoniqueJournal of Biological Chemistry (2006), 281 (18), 12799-12808CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer disease (AD). It has been hypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes and neurons. However, the regulation of the cholesterol supply of neurons via apoE-contg. high d. lipoproteins remains to be clarified. We show for the first time that the brain-specific metabolite of cholesterol produced by neurons, i.e. 24(S)-hydroxycholesterol, induces apoE transcription, protein synthesis, and secretion in a dose- and time-dependent manner in cells of astrocytic but not of neuronal origin. Moreover, 24(S)-hydroxycholesterol primes astrocytoma, but not neuroblastoma cells, to mediate cholesterol efflux to apoE. Similar results were obtained using the synthetic liver X receptor (LXR) agonist GW683965A, suggesting involvement of an LXR-controlled signaling pathway. A 10-20-fold higher basal LXRα and -β expression level in astrocytoma compared with neuroblastoma cells may underlie these differential effects. Furthermore, apoE-mediated cholesterol efflux from astrocytoma cells may be controlled by the ATP binding cassette transporters ABCA1 and ABCG1, since their expression was also up-regulated by both compds. In contrast, ABCG4 seems not to be involved, because its expression was induced only in neuronal cells. The expression of sterol regulatory element-binding protein (SREBP-2), low d. lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and SREBP-1c was transiently up-regulated by GW683965A in astrocytes but down-regulated by 24(S)-hydroxycholesterol, suggesting that cholesterol efflux and synthesis are regulated independently. In conclusion, evidence is provided that 24(S)-hydroxycholesterol induces apoE-mediated efflux of cholesterol in astrocytes via an LXR-controlled pathway, which may be relevant for chronic and acute neurol. diseases.
- 161Peet, D. J.; Turley, S. D.; Ma, W.; Janowski, B. A.; Lobaccaro, J. M. A.; Hammer, R. E.; Mangelsdorf, D. J. Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα. Cell 1998, 93 (5), 693– 704, DOI: 10.1016/S0092-8674(00)81432-4[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjsl2ksb4%253D&md5=3f79fdf5390184cff2f5ee4653676e04Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXRαPeet, Daniel J.; Turley, Stephen D.; Ma, Wenzhen; Janowski, Bethany A.; Lobaccaro, Jean-Marc A.; Hammer, Robert E.; Mangelsdorf, David J.Cell (Cambridge, Massachusetts) (1998), 93 (5), 693-704CODEN: CELLB5; ISSN:0092-8674. (Cell Press)We demonstrate that mice lacking the oxysterol receptor, LXRα, lose their ability to respond normally to dietary cholesterol and are unable to tolerate any amt. of cholesterol in excess of that which they synthesize de novo. When fed diets contg. cholesterol, LXRα (-/-) mice fail to induce transcription of the gene encoding cholesterol 7α-hydroxylase (Cyp7a), the rate-limiting enzyme in bile acid synthesis. This defect is assocd. with a rapid accumulation of large amts. of cholesterol in the liver that eventually leads to impaired hepatic function. The regulation of several other crucial lipid metabolizing genes is also altered in LXRα (-/-) mice. These results demonstrate the existence of a physiol. significant feed-forward regulatory pathway for sterol metab. and establish the role of LXRα as the major sensor of dietary cholesterol.
- 162Andersson, S.; Gustafsson, N.; Warner, M.; Gustafsson, J.-Å. Inactivation of Liver X Receptor β Leads to Adult-Onset Motor Neuron Degeneration in Male Mice. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (10), 3857– 3862, DOI: 10.1073/pnas.0500634102[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXisVOgtL8%253D&md5=7952398d57bc6e6ecbca679d45b2016aInactivation of liver X receptor β leads to adult-onset motor neuron degeneration in male miceAndersson, Sandra; Gustafsson, Nina; Warner, Margaret; Gustafsson, Jan-AkeProceedings of the National Academy of Sciences of the United States of America (2005), 102 (10), 3857-3862CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Male mice with inactivated liver X receptor (LXR) β suffer from adult-onset motor neuron degeneration. By 7 mo of age, motor coordination is impaired, and this condition is assocd. with lipid accumulation and loss of motor neurons in the spinal cord, together with axonal atrophy and astrogliosis. Several of these features are reminiscent of the neuropathol. signs of chronic motor neuron disease such as amyotrophic lateral sclerosis. Because the LXRs are important for cholesterol and lipid metab., we speculate that absence of LXRβ leads to pathol. accumulation of sterols and lipids that may themselves be neurotoxic or may modulate intracellular pathways and thereby predispose motor neurons to degeneration.
- 163Bigini, P.; Steffensen, K. R.; Ferrario, A.; Diomede, L.; Ferrara, G.; Barbera, S.; Salzano, S.; Fumagalli, E.; Ghezzi, P.; Mennini, T.; Gustafsson, J.-Å. Neuropathologic and Biochemical Changes During Disease Progression in Liver X Receptor β –/– Mice, A Model of Adult Neuron Disease. J. Neuropathol. Exp. Neurol. 2010, 69 (6), 593– 605, DOI: 10.1097/NEN.0b013e3181df20e1[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslWhtr0%253D&md5=2d9fa70c51471c2670561984bb2df98eNeuropathologic and Biochemical Changes During Disease Progression in Liver X Receptor β-/- Mice, A Model of Adult Neuron DiseaseBigini, Paolo; Steffensen, Knut R.; Ferrario, Anna; Diomede, Luisa; Ferrara, Giovanni; Barbera, Sara; Salzano, Sonia; Fumagalli, Elena; Ghezzi, Pietro; Mennini, Tiziana; Gustafsson, Jan-ÅkeJournal of Neuropathology & Experimental Neurology (2010), 69 (6), 593-605CODEN: JNENAD; ISSN:0022-3069. (Lippincott Williams & Wilkins)In amyotrophic lateral sclerosis (ALS), there is selective degeneration of motor neurons that leads to paralysis and death. Although the etiol. of ALS is unclear, its heterogeneity suggests that a combination of factors (endogenous and/or environmental) may induce progressive motor neuron stress that results in the activation of different cell death pathways. Alterations of brain cholesterol homeostasis have recently been considered as possible cofactors in many neurodegenerative disorders, including ALS. The liver X receptor β (LXRβ) receptor is involved in lipogenesis and cholesterol metab., and we previously found that adult-onset motor neuron pathol. occurs in LXRβ mice. Here, we investigated neuromuscular alterations of LXRβ mice from ages 3 to 24 mo. Increased cholesterol levels, gliosis, and inflammation preceded motor neuron loss and clin. disease onset; the mice showed progressive motor neuron deficits starting from age 7 mo. The nos. of motor neurons and neuromuscular junctions were decreased in 24-mo-old mice, but neither paralysis nor reduced life span was obsd. Moreover, other spinal neurons were also lost in these mice. These results suggest that LXRβ may inhibit neuroinflammation and maintain cholesterol homeostasis, and that LXRβ mice represent a potential model for investigating the role of cholesterol in ALS and other neurodegenerative disorders.
- 164Meffre, D.; Shackleford, G.; Hichor, M.; Gorgievski, V.; Tzavara, E. T.; Trousson, A.; Ghoumari, A. M.; Deboux, C.; Oumesmar, B. N.; Liere, P.; Schumacher, M.; Baulieu, E.-E.; Charbonnier, F.; Grenier, J.; Massaad, C. Liver X Receptors Alpha and Beta Promote Myelination and Remyelination in the Cerebellum. Proc. Natl. Acad. Sci. U. S. A. 2015, 112 (24), 7587– 7592, DOI: 10.1073/pnas.1424951112[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptFShsL4%253D&md5=1835e42bc70fc4c62c299aedb6dfdb6cLiver X receptors alpha and beta promote myelination and remyelination in the cerebellumMeffre, Delphine; Shackleford, Ghjuvan'Ghjacumu; Hichor, Mehdi; Gorgievski, Victor; Tzavara, Eleni T.; Trousson, Amalia; Ghoumari, Abdel M.; Deboux, Cyrille; Oumesmar, Brahim Nait; Liere, Philippe; Schumacher, Michael; Baulieu, Etienne-Emile; Charbonnier, Frederic; Grenier, Julien; Massaad, CharbelProceedings of the National Academy of Sciences of the United States of America (2015), 112 (24), 7587-7592CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The identification of new pathways governing myelination provides innovative avenues for remyelination. Liver X receptors (LXRs) α and β are nuclear receptors activated by oxysterols that originated from the oxidn. of cholesterol. They are crucial for cholesterol homeostasis, a major lipid constituent of myelin sheaths that are formed by oligodendrocytes. However, the role of LXRs in myelin generation and maintenance is poorly understood. Here, we show that LXRs are involved in myelination and remyelination processes. LXRs and their ligands are present in oligodendrocytes. We found that mice invalidated for LXRs exhibit altered motor coordination and spatial learning, thinner myelin sheaths, and reduced myelin gene expression. Conversely, activation of LXRs by either 25-hydroxycholesterol or synthetic TO901317 stimulates myelin gene expression at the promoter, mRNA, and protein levels, directly implicating LXRα/β in the transcriptional control of myelin gene expression. Interestingly, activation of LXRs also promotes oligodendroglial cell maturation and remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Together, our findings represent a conceptual advance in the transcriptional control of myelin gene expression and strongly support a new role of LXRs as pos. modulators in central (re)myelination processes.
- 165Song, X.-Y.; Wu, W.-F.; Gabbi, C.; Dai, Y.-B.; So, M.; Chaurasiya, S. P.; Wang, L.; Warner, M.; Gustafsson, J. Å. Retinal and Optic Nerve Degeneration in Liver X Receptor β Knockout Mice. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (33), 16507– 16512, DOI: 10.1073/pnas.1904719116[Crossref], [PubMed], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFylsLfJ&md5=9c9c2d8ee91b742de28c7018f3009e9bRetinal and optic nerve degeneration in liver X receptor β knockout miceSong, Xiao-yu; Wu, Wan-fu; Gabbi, Chiara; Dai, Yu-bing; So, Mark; Chaurasiya, Surendra P.; Wang, Li; Warner, Margaret; Gustafsson, Jan-AakeProceedings of the National Academy of Sciences of the United States of America (2019), 116 (33), 16507-16512CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The retina is an extension of the brain. Like the brain, neurodegeneration of the retina occurs with age and is the cause of several retinal diseases including optic neuritis, macular degeneration, and glaucoma. Liver X receptors (LXRs) are expressed in the brain where they play a key role in maintenance of cerebrospinal fluid and the health of dopaminergic neurons. Herein, we report that LXRs are expressed in the retina and optic nerve and that loss of LXRβ, but not LXRα, leads to loss of ganglion cells in the retina. In the retina of LXRβ-/- mice, there is an increase in amyloid A4 and deposition of beta-amyloid (Aβ) aggregates but no change in the level of apoptosis or autophagy in the ganglion cells and no activation of microglia or astrocytes. However, in the optic nerve there is a loss of aquaporin 4 (AQP4) in astrocytes and an increase in activation of microglia. Since loss of AQP4 and microglial activation in the optic nerve precedes the loss of ganglion cells, and accumulation of Aβ in the retina, the cause of the neuronal loss appears to be optic nerve degeneration. In patients with optic neuritis there are frequently AQP4 autoantibodies which block the function of AQP4. LXRβ-/- mouse is another model of optic neuritis in which AQP4 antibodies are not detectable, but AQP4 function is lost because of redn. in its expression.
- 166Zelcer, N.; Khanlou, N.; Clare, R.; Jiang, Q.; Reed-Geaghan, E. G.; Landreth, G. E.; Vinters, H. V.; Tontonoz, P. Attenuation of Neuroinflammation and Alzheimer’s Disease Pathology by Liver x Receptors. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (25), 10601– 10606, DOI: 10.1073/pnas.0701096104[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnt1Oisrs%253D&md5=2e39b726deba9673ce5a76f2e864789eAttenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptorsZelcer, Noam; Khanlou, Negar; Clare, Ryan; Jiang, Qingguang; Reed-Geaghan, Erin G.; Landreth, Gary E.; Vinters, Harry V.; Tontonoz, PeterProceedings of the National Academy of Sciences of the United States of America (2007), 104 (25), 10601-10606CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metab. and inflammation, processes that can be modulated by liver x receptors (LXRs). We show here that endogenous LXR signaling impacts the development of AD-related pathol. Genetic loss of either Lxrα or Lxrβ in APP/PS1 transgenic mice results in increased amyloid plaque load. LXRs regulate basal and inducible expression of key cholesterol homeostatic genes in the brain and act as potent inhibitors of inflammatory gene expression. Ligand activation of LXRs attenuates the inflammatory response of primary mixed glial cultures to fibrillar amyloid β peptide (fAβ) in a receptor-dependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fAβ-stimulated phagocytosis in the setting of inflammation. These results identify endogenous LXR signaling as an important determinant of AD pathogenesis in mice. We propose that LXRs may be tractable targets for the treatment of AD due to their ability to modulate both lipid metabolic and inflammatory gene expression in the brain.
- 167Cui, W.; Sun, Y.; Wang, Z.; Xu, C.; Peng, Y.; Li, R. Liver X Receptor Activation Attenuates Inflammatory Response and Protects Cholinergic Neurons in APP/PS1 Transgenic Mice. Neuroscience 2012, 210, 200– 210, DOI: 10.1016/j.neuroscience.2012.02.047[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xntlahsbo%253D&md5=853f54f01e6dc13814e7497df19636c8Liver X receptor activation attenuates inflammatory response and protects cholinergic neurons in APP/PS1 transgenic miceCui, W.; Sun, Y.; Wang, Z.; Xu, C.; Peng, Y.; Li, R.Neuroscience (Amsterdam, Netherlands) (2012), 210 (), 200-210CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)Alzheimer's disease (AD) is assocd. with beta-amyloid deposition, glial activation, and increased levels of the cytokines, as well as cholinergic dysfunction. Liver X receptor (LXR) has been found to inhibit the expression of pro-inflammatory genes. However, the effects of LXR activation on inflammatory response and on cholinergic system in AD are not yet clear. The present results revealed that LXR activation markedly attenuated several inflammatory markers and decreased microglial activation and reactive astrocytes in amyloid precursor protein (APP)/PS1 transgenic mice. Addnl., LXR activation significantly increased the no. of cholinergic neurons in the medial septal regions and the basal nucleus of Meynert (NBM), and attenuated cognitive impairment. Furthermore, we obsd. that LXR activation inhibited the prodn. of COX-2 and iNOS from Aβ25-35-induced microglia. LXR activation and nuclear factor kappa B (NF-κB) inhibitor PDTC both attenuated Aβ25-35 induction of NF-κB activation. These results suggest that LXR agonists suppress the prodn. of pro-inflammatory mols., at least in part, by modulating NF-κB-signaling pathway. Collectively, these studies suggest that LXR agonists may have therapeutic significance in AD.
- 168Strittmatter, W. J.; Saunders, A. M.; Schmechel, D.; Pericak-Vance, M.; Enghild, J.; Salvesen, G. S.; Roses, A. D. Apolipoprotein E: High-Avidity Binding to β-Amyloid and Increased Frequency of Type 4 Allele in Late-Onset Familial Alzheimer Disease. Proc. Natl. Acad. Sci. U. S. A. 1993, 90 (5), 1977– 1981, DOI: 10.1073/pnas.90.5.1977[Crossref], [PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXhs1Klsrs%253D&md5=a9c5fafcf128fc2c9dbe4f66a26d1981Apolipoprotein E: High-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer diseaseStrittmatter, Warren J.; Saunders, Ann M.; Schmechel, Donald; Pericak-Vance, Margaret; Enghild, Jan; Salvesen, Guy S.; Roses, Allen D.Proceedings of the National Academy of Sciences of the United States of America (1993), 90 (5), 1977-81CODEN: PNASA6; ISSN:0027-8424.Apolipoprotein E is immunochem. localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic βA4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-18 of the βA4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously assocd. with linkage of late-onset familial Alzheimer disease. Anal. of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant assocn. of apolipoprotein E type 4 allele (APOE-ε4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-ε4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50; the allele frequency of APOE-ε4 in 91 age-matched unrelated controls was 0.16 (Z = 2.44, P = 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.
- 169Pitas, R. E.; Boyles, J. K.; Lee, S. H.; Foss, D.; Mahley, R. W. Astrocytes Synthesize Apolipoprotein E and Metabolize Apolipoprotein E-Containing Lipoproteins. Biochim. Biophys. Acta, Lipids Lipid Metab. 1987, 917 (1), 148– 161, DOI: 10.1016/0005-2760(87)90295-5[Crossref], [PubMed], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2sXot1SntA%253D%253D&md5=9b8e51955e70b3ca56db292e5ec9efb0Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteinsPitas, Robert E.; Boyles, Janet K.; Lee, Susan H.; Foss, Donna; Mahley, Robert W.Biochimica et Biophysica Acta, Lipids and Lipid Metabolism (1987), 917 (1), 148-61CODEN: BBLLA6; ISSN:0005-2760.Primary cultures of rat brain astrocytes were used to study apolipoprotein E synthesis, secretion, and metab. in vitro. The astrocytes in culture contained immunoreactive apolipoprotein E in the area of the Golgi app. Incubation of the astrocytes with [35S]methionine resulted in the secretion of labeled immunoprecipitable apolipoprotein E, which constituted 1-3% of the total secreted proteins. The apolipoprotein E secreted in culture and the apolipoprotein E in rat brain exts. differed from serum apolipoprotein E in 2 respects: both had a slightly higher apparent mol. wt. (∼36,000) and more acidic isoforms than serum apolipoprotein E. Sialylation of the newly secreted apolipoprotein accounted for the difference in both the apparent mol. wt. and isoelec. focusing pattern of newly secreted apolipoprotein E and plasma apolipoprotein E. The astrocytes possessed apolipoprotein B,E[low-d. lipoprotein(LDL)] receptors capable of binding and internalizing apolipoprotein E-contg. lipoproteins. The uptake of lipoproteins by the cells led to a redn. in the no. of cell surface receptors and to the intracellular accumulation of cholesteryl esters. Since apolipoprotein E is present within the brain, and since brain cells can express apolipoprotein B,E(LDL) receptors, apolipoprotein E-contg. lipoproteins may function to redistribute lipid and regulate cholesterol homeostasis within the brain.
- 170Ignatius, M. J.; Gebicke-Harter, P. J.; Skene, J. H.; Schilling, J. W.; Weisgraber, K. H.; Mahley, R. W.; Shooter, E. M. Expression of Apolipoprotein E during Nerve Degeneration and Regeneration. Proc. Natl. Acad. Sci. U. S. A. 1986, 83 (4), 1125– 1129, DOI: 10.1073/pnas.83.4.1125[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL28Xht1OgsLw%253D&md5=6f97affa572e92c94c4233e8ebfdfa2cExpression of apolipoprotein E during nerve degeneration and regenerationIgnatius, Michael J.; Gebicke-Haerter, Peter J.; Skene, J. H. Pate; Schilling, James W.; Weisgraber, Karl H.; Mahley, Robert W.; Shooter, Eric M.Proceedings of the National Academy of Sciences of the United States of America (1986), 83 (4), 1125-9CODEN: PNASA6; ISSN:0027-8424.A 37-kilodalton (kDa) glycoprotein, the synthesis of which is dramatically increased after injury of the rat sciatic and optic nerves, has been recently described. Extensive homol. was found between the 37-kDa nerve injury-induced protein and a well-studied serum protein, apolipoprotein E (apoE), that is involved in lipid and cholesterol metab. and that has been shown recently to be present in adult and developing rat astroglia. Both proteins had identical isoelec. focusing points and similar mol. masses. Antibodies raised against the 37-kDa protein recognized apoE and anti-apoE serum crossreacted with the 37-kDa protein. Sequence data for 2 14-amino acid stretches of the 37-kDa protein matched identical regions of apoE. Evidently, the 37-kDa protein is identical to serum apoE and could have functions similar to the latter.
- 171Fukumoto, H.; Deng, A.; Irizarry, M. C.; Fitzgerald, M. L.; Rebeck, G. W. Induction of the Cholesterol Transporter ABCA1 in Central Nervous System Cells by Liver X Receptor Agonists Increases Secreted Aβ Levels. J. Biol. Chem. 2002, 277 (50), 48508– 48513, DOI: 10.1074/jbc.M209085200[Crossref], [PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xptlegt7w%253D&md5=f1051a16f6d6e56e0f5f7d703a0f41c7Induction of the Cholesterol Transporter ABCA1 in Central Nervous System Cells by Liver X Receptor Agonists Increases Secreted Aβ LevelsFukumoto, Hiroaki; Deng, Amy; Irizarry, Michael C.; Fitzgerald, Michael L.; Rebeck, G. WilliamJournal of Biological Chemistry (2002), 277 (50), 48508-48513CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The expression, function, and regulation of the cholesterol efflux mol., ABCA1, has been extensively examd. in peripheral tissues but only poorly studied in the brain. Brain cholesterol metab. is of interest because several lines of evidence suggest that elevated cholesterol increases the risk of Alzheimer's disease. We found a largely neuronal expression of ABCA1 in normal rat brain by in situ hybridization. ABCA1 message was dramatically up-regulated in neurons and glia in areas of damage by hippocampal AMPA lesion after 3-7 days. Immunoblot anal. demonstrated ABCA1 protein in cultured neuronal and glial cells, and expression was induced by ligands of the nuclear hormone receptors of the retinoid X receptor and liver X receptor family. ABCA1 was induced by treatment with retinoic acid and several oxysterols, including 22(R)-hydroxycholesterol and 24-hydroxycholesterol. Expression of an ABCA1-green fluorescent protein construct in neuroblastoma cells demonstrated fluorescence in perinuclear compartments and on the plasma membrane. Because the Aβ peptide is important in Alzheimer's disease pathogenesis, we examd. whether ABCA1 induction altered Aβ levels. Treatment of neuroblastoma cells with retinoic acid and 22(R)-hydroxycholesterol caused significant increases in secreted Aβ40 (29%) and Aβ42 (65%). Treatment with a nonsteroidal liver X receptor ligand, TO-901317, similarly increased levels of secreted Aβ40 (25%) and Aβ42 (126%). The increase in secreted Aβ levels was reduced by RNAi blocking of ABCA1 expression. These data suggest that the cholesterol efflux mol. ABCA1 may also be involved in the secretion of the membrane-assocd. mol., Aβ.
- 172Sun, Y.; Yao, J.; Kim, T.-W.; Tall, A. R. Expression of Liver X Receptor Target Genes Decreases Cellular Amyloid β Peptide Secretion. J. Biol. Chem. 2003, 278 (30), 27688– 27694, DOI: 10.1074/jbc.M300760200[Crossref], [PubMed], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXlsFKktL4%253D&md5=6446e277ab3b67d722fcaca51363a6d5Expression of Liver X Receptor Target Genes Decreases Cellular Amyloid β Peptide SecretionSun, Yu; Yao, Jun; Kim, Tae-Wan; Tall, Alan R.Journal of Biological Chemistry (2003), 278 (30), 27688-27694CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)A hallmark of Alzheimer's disease is the deposition of plaques of amyloid β peptide (Aβ) in the brain. Aβ is thought to be formed from the amyloid precursor protein (APP) in cholesterol-enriched membrane rafts, and cellular cholesterol depletion decreases Aβ formation. The liver X receptors (LXR) play a key role in regulating genes that control cellular cholesterol efflux and membrane compn. and are widely expressed in cells of the central nervous system. We show that treatment of APP-expressing cells with LXR activators reduces the formation of Aβ. LXR activation resulted in increased levels of the ATP-binding cassette transporter A1 (ABCA1) and stearoyl CoA desaturase, and expression of these genes individually decreased formation of Aβ. Expression of ABCA1 led to both decreased β-cleavage product of APPSw (i.e. C99 peptide) and reduced γ-secretase-cleavage of C99 peptide. Remarkably, these effects of ABCA1 on APP processing were independent of cellular lipid efflux. LXR and ABCA1-induced changes in membrane lipid organization had favorable effects on processing of APP, suggesting a new approach to the treatment of Alzheimer's disease.
- 173Koldamova, R. P.; Lefterov, I. M.; Staufenbiel, M.; Wolfe, D.; Huang, S.; Glorioso, J. C.; Walter, M.; Roth, M. G.; Lazo, J. S. The Liver X Receptor Ligand T0901317 Decreases Amyloid β Production in Vitro and in a Mouse Model of Alzheimer’s Disease. J. Biol. Chem. 2005, 280 (6), 4079– 4088, DOI: 10.1074/jbc.M411420200[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVyntLc%253D&md5=8657c90b7ef8247998470773ed5f024bThe Liver X Receptor Ligand T0901317 Decreases Amyloid β Production in Vitro and in a Mouse Model of Alzheimer's DiseaseKoldamova, Radosveta P.; Lefterov, Iliya M.; Staufenbiel, Matthias; Wolfe, Darren; Huang, Shaohua; Glorioso, Joseph C.; Walter, Michael; Roth, Michael G.; Lazo, John S.Journal of Biological Chemistry (2005), 280 (6), 4079-4088CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Recent studies indicate that oxysterols, which are ligands for the nuclear hormone liver X receptors (LXR), decrease amyloid β (Aβ) secretion in vitro. The effect was attributed primarily to the ATP-binding cassette transporter A1 (ABCA1) transcriptionally up-regulated by ligand-activated LXRs. The authors now examd. the effect of the synthetic LXR ligand T0901317, which can be used in vivo, on Aβ prodn. in vitro and in APP23 transgenic mice. T0901317 applied to a variety of in vitro models, including immortalized fibroblasts from Tangier patients, and primary embryonic mouse neurons caused a concn.-dependent decrease in Aβ secretion, and this effect was increased by the addn. of apolipoprotein A-I. The inhibition of Aβ prodn. by T0901317 was cell-type specific, being more prominent in primary neurons than in nonneuronal cells. Tangier fibroblasts lacking a functional ABCA1 secreted more Aβ than control fibroblasts, thus demonstrating the role of ABCA1 in amyloid precursor protein (APP) processing and Aβ generation. T0901317 treatment of 11-wk-old APP23 mice for 6 days showed a significant increase in ABCA1 expression and a decrease in the ratio of sol. APP (sAPP)β- to sAPPα-cleavage products. Most importantly, the treatment caused a statistically significant redn. in the levels of sol. Aβ40 and of Aβ42 in the brain these mice. Our expts. demonstrate that T0901317 decreases amyloidogenic processing of APP in vitro and in vivo, thus supporting the search for potent and specific LXR ligands with properties allowing therapeutic application.
- 174Fitz, N. F.; Cronican, A.; Pham, T.; Fogg, A.; Fauq, A. H.; Chapman, R.; Lefterov, I.; Koldamova, R. Liver X Receptor Agonist Treatment Ameliorates Amyloid Pathology and Memory Deficits Caused by High-Fat Diet in APP23 Mice. J. Neurosci. 2010, 30 (20), 6862– 6872, DOI: 10.1523/JNEUROSCI.1051-10.2010[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovVWnurc%253D&md5=dee2ded5f2bf53a49f5621a618fe75a1Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 miceFitz, Nicholas F.; Cronican, Andrea; Pham, Tam; Fogg, Allison; Fauq, Abdul H.; Chapman, Robert; Lefterov, Iliya; Koldamova, RadosvetaJournal of Neuroscience (2010), 30 (20), 6862-6872CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)High-fat diet and certain dietary patterns are assocd. with higher incidence of sporadic Alzheimer's disease (AD) and cognitive decline. However, no specific therapy has been suggested to ameliorate the neg. effects of high fat/high cholesterol levels on cognition and amyloid pathol. Here we show that in 9-mo-old APP23 mice, a high-fat/high-cholesterol (HF) diet provided for 4 mo exacerbates the AD phenotype evaluated by behavioral, morphol., and biochem. assays. To examine the therapeutic potential of liver X receptor (LXR) ligands, APP23 mice were fed HF diet supplemented with synthetic LXR agonist T0901317 (T0). Our results demonstrate that LXR ligand treatment causes a significant redn. of memory deficits obsd. during both acquisition and retention phases of the Morris water maze. Moreover, the effects of T0 on cognition correlate with AD-like morphol. and biochem. parameters. We found a significant decrease in amyloid plaque load, insol. Aβ and sol. Aβ oligomers. In vitro expts. with primary glia demonstrate that Abca1 is essential for the proper lipidation of ApoE and mediates the effects of T0 on Aβ degrdn. by microglia. Microdialysis expts. performed on awake freely moving mice showed that T0 decreased Aβ levels in the interstitial fluid of the hippocampus, supporting the conclusion that this treatment increases Aβ clearance. The data presented conclusively shows that LXR activation in the context of a metabolic challenge has crit. effects on AD phenotype progression by attenuating Aβ deposition and facilitating its clearance.
- 175Cui, W.; Sun, Y.; Wang, Z.; Xu, C.; Xu, L.; Wang, F.; Chen, Z.; Peng, Y.; Li, R. Activation of Liver x Receptor Decreases BACE1 Expression and Activity by Reducing Membrane Cholesterol Levels. Neurochem. Res. 2011, 36 (10), 1910– 1921, DOI: 10.1007/s11064-011-0513-3[Crossref], [PubMed], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmslymsb4%253D&md5=aae2a483da4c4b349b0b8e79166890beActivation of liver X receptor decreases BACE1 expression and activity by reducing membrane cholesterol levelsCui, Weigang; Sun, Yan; Wang, Zhongping; Xu, Chongchong; Xu, Li; Wang, Fei; Chen, Zulin; Peng, Yuwen; Li, RuixiNeurochemical Research (2011), 36 (10), 1910-1921CODEN: NEREDZ; ISSN:0364-3190. (Springer)The synthetic Liver X receptor (LXR) activator T0901317 has been reported to exert neuroprotective effect in Alzheimer's disease, but the relationship between LXR activation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) remains uncertain. This study investigated the effect of T0901317 on membrane cholesterol levels, BACE1 expression and activity. We found that T0901317 decreased membrane cholesterol levels, reduced BACE1 expression and activity as well as β-secretase cleaved C-terminal fragment (β-CTF) levels in vivo and in vitro. Meanwhile, the expression of ATP-binding membrane cassette transport protein A1 (ABCA1) enhanced. Addnl., inhibition of ABCA1 abrogated the effects of T0901317 on membrane cholesterol levels and β-secretase activity. Moreover, addn. of LXR antagonist reversed the effect of T0901317 on ABCA1 mRNA expression, membrane cholesterol levels and β-secretase activity. Our results suggest that activation of LXR may decrease BACE1 expression and activity through a pathway assocd. with ABCA1-mediated redn. in membrane cholesterol levels.
- 176Wang, Q.; Wang, S.; Shi, Y.; Yao, M.; Hou, L.; Jiang, L. Reduction of Liver X Receptor β Expression in Primary Rat Neurons by Antisense Oligodeoxynucleotides Decreases Secreted Amyloid β Levels. Neurosci. Lett. 2014, 561, 146– 150, DOI: 10.1016/j.neulet.2013.12.055[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVWrtbw%253D&md5=6bf4cc34a1ff79d2ab2925bc054c469eReduction of Liver X Receptor β expression in primary rat neurons by antisense oligodeoxynucleotides decreases secreted amyloid β levelsWang, Qie; Wang, Suling; Shi, Yun; Yao, Min; Hou, Lianguo; Jiang, LinglingNeuroscience Letters (2014), 561 (), 146-150CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Ligand-activated Liver X Receptor (LXR) is known to increase cholesterol efflux from cells and reduce the prodn. of amyloid β (Aβ) from amyloid-beta precursor protein (APP). However, little is known about the effects of LXRβ, one subtype of LXR, on endogenous Aβ. In this study, we show that LXRβ inactivation with specific antisense oligodeoxynucleotides (As-ODN) significantly reduced secreted Aβ and decreased mRNA levels of APP751+770, and α-, β-secretase (ADAM10, BACE1) in primary rat neurons. We also show that As-ODN down-regulated the LXR responsive genes ABCA1 and HMG-CoA reductase (HMGCR). These changes are assocd. with decreased cellular cholesterol levels. The effect of LXRβ inactivation on Aβ levels is likely due to the alteration of cholesterol prodn. and APP processing. Thus, our data suggest that LXRβ has an important function in cholesterol homeostasis and endogenous Aβ maintenance in neurons.
- 177Vanmierlo, T.; Rutten, K.; Dederen, J.; Bloks, V. W.; van Vark-van der Zee, L. C.; Kuipers, F.; Kiliaan, A.; Blokland, A.; Sijbrands, E. J. G.; Steinbusch, H.; Prickaerts, J.; Lütjohann, D.; Mulder, M. Liver X Receptor Activation Restores Memory in Aged AD Mice without Reducing Amyloid. Neurobiol. Aging 2011, 32 (7), 1262– 1272, DOI: 10.1016/j.neurobiolaging.2009.07.005[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntlGjt7k%253D&md5=fa153f5dedceb7e40c084e4d6a14bcb4Liver X receptor activation restores memory in aged AD mice without reducing amyloidVanmierlo, Tim; Rutten, Kris; Dederen, Jos; Bloks, Vincent W.; van Vark-van der Zee, Leonie C.; Kuipers, Folkert; Kiliaan, Amanda; Blokland, Arjan; Sijbrands, Eric J. G.; Steinbusch, Harry; Prickaerts, Jos; Luetjohann, Dieter; Mulder, MoniqueNeurobiology of Aging (2011), 32 (7), 1262-1272CODEN: NEAGDO; ISSN:0197-4580. (Elsevier)Alterations in cerebral cholesterol metab. are thought to play a role in the progression of Alzheimer's disease (AD). Liver X receptors (LXRs) are key regulators of cholesterol metab. The synthetic LXR activator, T0901317 has been reported to improve memory functions in animal models for AD and to reduce amyloid-β (Aβ) deposition in the brain. Here we provide evidence that long-term administration of T0901317 to aged, 21-mo-old APPSLxPS1mut mice restores impaired memory. Cerebral cholesterol turnover was enhanced as indicated by the increased levels of brain cholesterol precursors and the upregulation of LXR-target genes Abca1, Abcg1, and Apoe. Unexpectedly, the improved memory functions in the APPSLxPS1mut mice after T0901317 treatment were not accompanied by a decrease in Aβ plaque load in the cortex or hippocampus DG, CA1 or CA3. T0901317 administration also enhanced cerebral cholesterol turnover in aged C57BL/6NCrl mice, but did not further improve their memory functions. In conclusion, long-term activation of the LXR-pathway restored memory functions in aged APPSLxPS1mut mice with advanced Aβ deposition. However the beneficial effects of T0901317 on memory in the APPSLxPS1mut mice were independent of the Aβ plaque load in the hippocampus, but were assocd. with enhanced brain cholesterol turnover.
- 178Sandoval-Hernández, A. G.; Buitrago, L.; Moreno, H.; Cardona-Gómez, G. P.; Arboleda, G. Role of Liver X Receptor in AD Pathophysiology. PLoS One 2015, 10 (12), e0145467, DOI: 10.1371/journal.pone.0145467[Crossref], [PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksFSjsr0%253D&md5=e9c8dc97778ff0d2afd1f0f48aa9da10Role of liver X receptor in AD pathophysiologySandoval-Hernandez, Adrian G.; Buitrago, Luna; Moreno, Herman; Cardona-Gomez, Gloria Patricia; Arboleda, GonzaloPLoS One (2015), 10 (12), e0145467/1-e0145467/24CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacol. activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are assocd. with improvement in cognition and redn. of amyloid beta pathol. in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-mo-old; three months treatment). The data suggests that the LXR agonist GW3965 is assocd. with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable redn. of the amyloid load. We also report that most cells overexpressing ApoE (86 ± 12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also obsd. redn. in astrogliosis and increased no. of stem and proliferating cells in the subgranular zone of the dentate gyrus. Addnl., we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/mol. mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.
- 179Báez-Becerra, C.; Filipello, F.; Sandoval-Hernández, A.; Arboleda, H.; Arboleda, G. Liver X Receptor Agonist GW3965 Regulates Synaptic Function upon Amyloid Beta Exposure in Hippocampal Neurons. Neurotoxic. Res. 2018, 33 (4), 569– 579, DOI: 10.1007/s12640-017-9845-3[Crossref], [PubMed], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlGltg%253D%253D&md5=d0aea58662132947b8c67aba38394808Liver X Receptor Agonist GW3965 Regulates Synaptic Function upon Amyloid Beta Exposure in Hippocampal NeuronsBaez-Becerra, C.; Filipello, F.; Sandoval-Hernandez, A.; Arboleda, H.; Arboleda, G.Neurotoxicity Research (2018), 33 (3), 569-579CODEN: NURRFI; ISSN:1029-8428. (Springer)Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by beta-amyloid (Aβ) accumulation and neurofibrillary tangles formation in the brain which are assocd. to synaptic deficits and dementia. Liver X receptor (LXR) agonists have been demonstrated to revert of pathol. and cognitive defects in murine models of AD through the regulation of Apolipoprotein E, ATP-Binding Cassette A1 (ABCA1), by dampening neuroinflammation and also by reducing the levels of amyloid-β (Aβ) accumulation in the brain. However, the role of LXR with regard to the regulation of synaptic function remains relatively understudied. In the present paper, we analyzed the in-vitro effect of the LXR agonist GW3965 on synaptic function upon exposure of primary hippocampal cultures to oligomeric amyloid-β (oAβ(1-42)). We showed that oAβ(1-42) exposure significantly decreased the d. of mature (mushroom shaped) dendritic spines d. and synaptic contacts no. oAβ(1-42) also modulates the expression of pre- (VGlut1, SYT1, SV2A) and post-synaptic (SHANK2, NMDA) proteins, it decreases the expression of PINK1, and increases ROCKII, and activates of caspase-3; these changes were prevented by the pre-treating neuronal cultures with GW3965. These results show further support the role of the LXR agonist GW3965 in synaptic physiol. and highlight its potential as an alternative pharmacol. strategy for AD.
- 180Kumar, N.; Solt, L. A.; Conkright, J. J.; Wang, Y.; Istrate, M. A.; Busby, S. A.; Garcia-Ordonez, R. D.; Burris, T. P.; Griffin, P. R. The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2- Trifluoro-1-Hydroxy-1-(Trifluoromethyl)Ethyl]Phenyl]-Benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist. Mol. Pharmacol. 2010, 77 (2), 228– 236, DOI: 10.1124/mol.109.060905[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFeitLk%253D&md5=04aaf2bdef4b9d64340e221f85838665The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-α/γ inverse agonistKumar, Naresh; Solt, Laura A.; Conkright, Juliana J.; Wang, Yongjun; Istrate, Monica A.; Busby, Scott A.; Garcia-Ordonez, Ruben D.; Burris, Thomas P.; Griffin, Patrick R.Molecular Pharmacology (2010), 77 (2), 228-236CODEN: MOPMA3; ISSN:0026-895X. (American Society for Pharmacology and Experimental Therapeutics)Retinoic acid receptor-related orphan receptors (RORs) regulate a variety of physiol. processes including hepatic gluconeogenesis, lipid metab., circadian rhythm, and immune function. Here we present the first high-affinity synthetic ligand for both RORα and RORγ. In a screen against all 48 human nuclear receptors, the benzenesulfonamide liver X receptor (LXR) agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) inhibited transactivation activity of RORα and RORγ but not RORβ. T0901317 was found to directly bind to RORα and RORγ with high affinity (Ki = 132 and 51 nM, resp.), resulting in the modulation of the receptor's ability to interact with transcriptional cofactor proteins. T0901317 repressed RORα/γ-dependent transactivation of ROR-responsive reporter genes and in HepG2 cells reduced recruitment of steroid receptor coactivator-2 by RORα at an endogenous ROR target gene (G6Pase). Using small interference RNA, we demonstrate that repression of the gluconeogenic enzyme glucose-6-phosphatase in HepG2 cells by T0901317 is ROR-dependent and is not due to the compd.'s LXR activity. In summary, T0901317 represents a novel chem. probe to examine RORα/γ function and an excellent starting point for the development of ROR selective modulators. More importantly, our results demonstrate that small mols. can be used to target the RORs for therapeutic intervention in metabolic and immune disorders.
- 181Dai, Y.-B.; Tan, X.-J.; Wu, W.-F.; Warner, M.; Gustafsson, J.-Å. Liver X Receptor β Protects Dopaminergic Neurons in a Mouse Model of Parkinson Disease. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (32), 13112– 13117, DOI: 10.1073/pnas.1210833109[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVWmsrfK&md5=07e2623bd636ee1bf6d6d65fa2a4eca7Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson diseaseDai, Yu-Bing; Tan, Xin-Jie; Wu, Wan-Fu; Warner, Margaret; Gustafsson, Jan-AkeProceedings of the National Academy of Sciences of the United States of America (2012), 109 (32), 13112-13117CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Parkinson disease (PD) is a progressive neurodegenerative disease whose progression may be slowed, but at present there is no pharmacol. intervention that would stop or reverse the disease. Liver X receptor β (LXRβ) is a member of the nuclear receptor super gene family expressed in the central nervous system, where it is important for cortical layering during development and survival of dopaminergic neurons throughout life. In the present study we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of LXRO as a target for prevention or treatment of PD. The dopaminergic neurons of the substantia nigra of LXRβ-/- mice were much more severely affected by MPTP than were those of their WT litter- mates. In addn., the no. of activated microglia and GFAP-pos. astrocytes was higher in the substantia nigra of LXRβ-/- mice than in WT littermates. Administration of the LXR agonist GW3965 to MPTP-treated WT mice protected against loss of dopa- minergic neurons and of dopaminergic fibers projecting to the striatum, and resulted in fewer activated microglia and astroglia. Surprisingly, LXRI was not expressed in the neurons of the substantia nigra but in the microglia and astroglia. We conclude that LXR agonists may have beneficial effects in treatment of PD by modulating the cytotoxic functions of microglia.
- 182Nelissen, K.; Mulder, M.; Smets, I.; Timmermans, S.; Smeets, K.; Ameloot, M.; Hendriks, J. J. A. Liver X Receptors Regulate Cholesterol Homeostasis in Oligodendrocytes. J. Neurosci. Res. 2012, 90 (1), 60– 71, DOI: 10.1002/jnr.22743[Crossref], [PubMed], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVKjsbvF&md5=d1d55372882978a9c6701863ce40536aLiver X receptors regulate cholesterol homeostasis in oligodendrocytesNelissen, Katherine; Mulder, Monique; Smets, Ilse; Timmermans, Silke; Smeets, Karen; Ameloot, Marcel; Hendriks, Jerome J. A.Journal of Neuroscience Research (2012), 90 (1), 60-71CODEN: JNREDK; ISSN:0360-4012. (Wiley-Liss, Inc.)Cholesterol synthesis and transport in oligodendrocytes are essential for optimal myelination and remyelination in pathol. conditions such as multiple sclerosis. However, little is known about cholesterol homeostasis in the myelin-forming oligodendrocytes. Liver X receptors (LXRs) are nuclear oxysterol receptors that regulate genes involved in cholesterol homeostasis and may therefore play an important role in de- and remyelination. We investigated whether LXRs regulate cholesterol homeostasis in oligodendrocytes. mRNA expression of genes encoding LXR-α and LXR-β and their target genes (ABCA1, ABCG1, ABCG4, apoE, and LDLR) was detected in oligodendrocytes derived from both neonatal and adult rats using quant. real-time PCR. The expression of LXR-β and several target genes was increased during oligodendrocyte differentiation. We further demonstrated that treatment of primary neonatal rat oligodendrocytes with the synthetic LXR agonist T0901317 induced the expression of several established LXR target genes, including ABCA1, ABCG1, apoE, and LDLR. Treatment of oligodendrocytes with T0901317 resulted in an enhanced cholesterol efflux in the presence of apolipoprotein A-I or high-d. lipoprotein particles. These data show that LXRs are involved in regulating cholesterol homeostasis in oligodendrocytes. © 2011 Wiley Periodicals, Inc.
- 183Berghoff, S. A.; Spieth, L.; Sun, T.; Hosang, L.; Schlaphoff, L.; Depp, C.; Düking, T.; Winchenbach, J.; Neuber, J.; Ewers, D.; Scholz, P.; van der Meer, F.; Cantuti-Castelvetri, L.; Sasmita, A. O.; Meschkat, M.; Ruhwedel, T.; Möbius, W.; Sankowski, R.; Prinz, M.; Huitinga, I.; Sereda, M. W.; Odoardi, F.; Ischebeck, T.; Simons, M.; Stadelmann-Nessler, C.; Edgar, J. M.; Nave, K.-A.; Saher, G. Microglia Facilitate Repair of Demyelinated Lesions via Post-Squalene Sterol Synthesis. Nat. Neurosci. 2021, 24 (1), 47– 60, DOI: 10.1038/s41593-020-00757-6[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1KktLrL&md5=6f3ea7774aa69a06d3a8f08587fe66ccMicroglia facilitate repair of demyelinated lesions via post-squalene sterol synthesisBerghoff, Stefan A.; Spieth, Lena; Sun, Ting; Hosang, Leon; Schlaphoff, Lennart; Depp, Constanze; Dueking, Tim; Winchenbach, Jan; Neuber, Jonathan; Ewers, David; Scholz, Patricia; van der Meer, Franziska; Cantuti-Castelvetri, Ludovico; Sasmita, Andrew O.; Meschkat, Martin; Ruhwedel, Torben; Moebius, Wiebke; Sankowski, Roman; Prinz, Marco; Huitinga, Inge; Sereda, Michael W.; Odoardi, Francesca; Ischebeck, Till; Simons, Mikael; Stadelmann-Nessler, Christine; Edgar, Julia M.; Nave, Klaus-Armin; Saher, GesineNature Neuroscience (2021), 24 (1), 47-60CODEN: NANEFN; ISSN:1097-6256. (Nature Research)Abstr.: The repair of inflamed, demyelinated lesions as in multiple sclerosis (MS) necessitates the clearance of cholesterol-rich myelin debris by microglia/macrophages and the switch from a pro-inflammatory to an anti-inflammatory lesion environment. Subsequently, oligodendrocytes increase cholesterol levels as a prerequisite for synthesizing new myelin membranes. We hypothesized that lesion resoln. is regulated by the fate of cholesterol from damaged myelin and oligodendroglial sterol synthesis. By integrating gene expression profiling, genetics and comprehensive phenotyping, we found that, paradoxically, sterol synthesis in myelin-phagocytosing microglia/macrophages dets. the repair of acutely demyelinated lesions. Rather than producing cholesterol, microglia/macrophages synthesized desmosterol, the immediate cholesterol precursor. Desmosterol activated liver X receptor (LXR) signaling to resolve inflammation, creating a permissive environment for oligodendrocyte differentiation. Moreover, LXR target gene products facilitated the efflux of lipid and cholesterol from lipid-laden microglia/macrophages to support remyelination by oligodendrocytes. Consequently, pharmacol. stimulation of sterol synthesis boosted the repair of demyelinated lesions, suggesting novel therapeutic strategies for myelin repair in MS.
- 184Mailleux, J.; Vanmierlo, T.; Bogie, J. F. J.; Wouters, E.; Lütjohann, D.; Hendriks, J. J. A.; van Horssen, J. Active Liver X Receptor Signaling in Phagocytes in Multiple Sclerosis Lesions. Mult. Scler. J. 2018, 24 (3), 279– 289, DOI: 10.1177/1352458517696595[Crossref], [PubMed], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvFOgtr4%253D&md5=1d65cb17f3433eb1701033621571376cActive liver X receptor signaling in phagocytes in multiple sclerosis lesionsMailleux, Jo; Vanmierlo, Tim; Bogie, Jeroen F. J.; Wouters, Elien; Lutjohann, Dieter; Hendriks, Jerome J. A.; van Horssen, JackMultiple Sclerosis Journal (2018), 24 (3), 279-289CODEN: MSJUAP; ISSN:1477-0970. (Sage Publications Ltd.)We sought to det. the liver X receptor (LXR) ligands present in human macrophages after myelin phagocytosis and whether LXRs are activated in multiple sclerosis (MS) lesions. We used real-time quant. polymerase chain reaction (PCR) and immunohistochem. to det. expression of LXRs and their response genes in human phagocytes after myelin phagocytosis and in active MS lesions. We used gas chromatog./mass spectrometric anal. to det. LXR-activating oxysterols and cholesterol precursors present and formed in myelin and myelin-incubated cells, resp. Myelin induced LXR response genes ABCA1 and ABCG1 in human monocyte-derived macrophages. In active MS lesions, we found that both gene expression and protein levels of ABCA1 and apolipoprotein E (APOE) are upregulated in foamy phagocytes. Moreover, we found that the LXR ligand 27-hydroxycholesterol (27OHC) is significantly increased in human monocyte-derived macrophages after myelin uptake. LXR response genes are upregulated in phagocytes present in active MS lesions, indicating that LXRs are activated in actively demyelinating phagocytes. In addn., we have shown that myelin contains LXR ligands and that 27OHC is generated in human monocyte-derived macrophages after myelin processing. This suggests that LXRs in phagocytes in active MS lesions are activated at least partially by (oxy)sterols present in myelin and the generation thereof during myelin processing.
- 185Cui, G.; Qin, X.; Wu, L.; Zhang, Y.; Sheng, X.; Yu, Q.; Sheng, H.; Xi, B.; Zhang, J. Z.; Zang, Y. Q. Liver X Receptor (LXR) Mediates Negative Regulation of Mouse and Human Th17 Differentiation. J. Clin. Invest. 2011, 121 (2), 658– 670, DOI: 10.1172/JCI42974[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsl2ru7c%253D&md5=dfaef076cb4e6e5b0d892c0c4d0057d8Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiationCui, Guoliang; Qin, Xia; Wu, Lili; Zhang, Yuebo; Sheng, Xiaoyan; Yu, Qiwen; Sheng, Hongguang; Xi, Beili; Zhang, Jingwu Z.; Zang, Ying QinJournal of Clinical Investigation (2011), 121 (2), 658-670CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)Th17 cells are a subset of CD4+ T cells with an important role in clearing certain bacterial and fungal pathogens. However, they have also been implicated in autoimmune diseases such as multiple sclerosis. Exposure of naive CD4+ T cells to IL-6 and TGF-β leads to Th17 cell differentiation through a process in which many proteins have been implicated. We report here that ectopic expression of liver X receptor (LXR) inhibits Th17 polarization of mouse CD4+ T cells, while LXR deficiency promotes Th17 differentiation in vitro. LXR activation in mice ameliorated disease in the exptl. autoimmune encephalomyelitis (EAE) model of multiple sclerosis, whereas LXR deficiency exacerbated disease. Further anal. revealed that Srebp-1, which is encoded by an LXR target gene, mediated the suppression of Th17 differentiation by binding to the E-box element on the Il17 promoter, phys. interacting with aryl hydrocarbon receptor (Ahr) and inhibiting Ahr-controlled Il17 transcription. The putative active site (PAS) domain of Ahr and the N-terminal acidic region of Srebp-1 were essential for this interaction. Addnl. analyses suggested that similar LXR-dependent mechanisms were operational during human Th17 differentiation in vitro. This study reports what we believe to be a novel signaling pathway underlying LXR-mediated regulation of Th17 cell differentiation and autoimmunity.
- 186Schultz, J. R.; Tu, H.; Luk, A.; Repa, J. J.; Medina, J. C.; Li, L.; Schwendner, S.; Wang, S.; Thoolen, M.; Mangelsdorf, D. J.; Lustig, K. D.; Shan, B. Role of LXRs in Control of Lipogenesis. Genes Dev. 2000, 14 (22), 2831– 2838, DOI: 10.1101/gad.850400[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXos1ehsLg%253D&md5=85a46e3313f736fe71de7c0da69f51c4Role of LXRs in control of lipogenesisSchultz, Joshua R.; Tu, Hua; Luk, Alvin; Repa, Joyce J.; Medina, Julio C.; Li, Leping; Schwendner, Susan; Wang, Shelley; Thoolen, Martin; Mangelsdorf, David J.; Lustig, Kevin D.; Shan, BeiGenes & Development (2000), 14 (22), 2831-2838CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)The discovery of oxysterols as the endogenous liver X receptor (LXR) ligands and subsequent gene targeting studies in mice provided strong evidence that LXR plays a central role in cholesterol metab. The identification here of a synthetic, nonsteroidal LXR-selective agonist series represented by T0314407 and T0901317 revealed a novel physiol. role of LXR. Oral administration of T0901317 to mice and hamsters showed that LXR activated the coordinate expression of major fatty acid biosynthetic genes (lipogenesis) and increased plasma triglyceride and phospholipid levels in both species. Complementary studies in cell culture and animals suggested that the increase in plasma lipids occurs via LXR-mediated induction of the sterol regulatory element-binding protein 1 (SREBP-1) lipogenic program.
- 187Collins, J. L.; Fivush, A. M.; Watson, M. A.; Galardi, C. M.; Lewis, M. C.; Moore, L. B.; Parks, D. J.; Wilson, J. G.; Tippin, T. K.; Binz, J. G.; Plunket, K. D.; Morgan, D. G.; Beaudet, E. J.; Whitney, K. D.; Kliewer, S. A.; Willson, T. M. Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary Amines. J. Med. Chem. 2002, 45 (10), 1963– 1966, DOI: 10.1021/jm0255116[ACS Full Text], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XivVOmu7w%253D&md5=296ce6aa3e3a49275b74d6b94b7304e8Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary AminesCollins, Jon L.; Fivush, Adam M.; Watson, Michael A.; Galardi, Cristin M.; Lewis, Michael C.; Moore, Linda B.; Parks, Derek J.; Wilson, Joan G.; Tippin, Tim K.; Binz, Jane G.; Plunket, Kelli D.; Morgan, Daniel G.; Beaudet, Elizabeth J.; Whitney, Karl D.; Kliewer, Steven A.; Willson, Timothy M.Journal of Medicinal Chemistry (2002), 45 (10), 1963-1966CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A potent, selective, orally active liver x receptor (LXR) agonist was identified from focused libraries of tertiary amines. GW3965 recruits the steroid receptor coactivator 1 to human LXRα in a cell-free ligand-sensing assay with an EC50 of 125 nM and profiles as a full agonist on hLXRα and hLXRβ in cell-based reporter gene assays with EC50's of 190 and 30 nM, resp. After oral dosing at 10 mg/kg to C57BL/6 mice, GW3965 increased expression of the reverse cholesterol transporter ABCA1 in the small intestine and peripheral macrophages and increased the plasma concns. of HDL cholesterol by 30%. GW3965 will be a valuable chem. tool to investigate the role of LXR in the regulation of reverse cholesterol transport and lipid metab.
- 188Kirchgessner, T. G.; Martin, R.; Sleph, P.; Grimm, D.; Liu, X.; Lupisella, J.; Smalley, J.; Narayanan, R.; Xie, Y.; Ostrowski, J.; Cantor, G. H.; Mohan, R.; Kick, E. Pharmacological Characterization of a Novel Liver X Receptor Agonist with Partial LXRα Activity and a Favorable Window in Nonhuman Primates. J. Pharmacol. Exp. Ther. 2015, 352 (2), 305– 314, DOI: 10.1124/jpet.114.219923[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFSqtb8%253D&md5=cc48fcf571e48e8f1ff417896b6d9ad0Pharmacological characterization of a novel liver X receptor agonist with partial LXRα activity and a favorable window in nonhuman primatesKirchgessner, Todd G.; Martin, Richard; Sleph, Paul; Grimm, Denise; Liu, Xiaoqin; Lupisella, John; Smalley, James; Narayanan, Rangaraj; Xie, Yinong; Ostrowski, Jacek; Cantor, Glenn H.; Mohan, Raju; Kick, EllenJournal of Pharmacology and Experimental Therapeutics (2015), 352 (2), 305-314/1-305-314/10, 10 pp.CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Liver X Receptors (LXRs) α and β are nuclear hormone receptors that regulate multiple genes involved in reverse cholesterol transport (RCT) and are potential drug targets for atherosclerosis. However, full pan agonists also activate lipogenic genes, resulting in elevated plasma and hepatic lipids. We report the pharmacol. of BMS-779788 [2-(2-(1-(2-chlorophenyl)-1-methylethyl)-1- (39-(methylsulfonyl)-4-biphenylyl)-1H-imidazol-4-yl)-2-propanol], a potent partial LXR agonist with LXRβ selectivity, which has an improved therapeutic window in the cynomolgus monkey compared with a full pan agonist. BMS-779788 induced LXR target genes in blood in vivo with an EC505610 nM, a value similar to its in vitro blood gene induction potency. BMS-779788 was 29- and 12-fold less potent than the full agonist T0901317 in elevating plasma triglyceride and LDL cholesterol, resp., with similar results for plasma cholesteryl ester transfer protein and apolipoprotein B. However, ABCA1 and ABCG1 mRNA inductions in blood, which are crit. for RCT,were comparable. Increased liver triglyceride was obsd. after 7-day treatment with BMS-779788 at the highest dose tested and was nearly identical to the dose response for plasma triglyceride, consistent with the central role of liver LXR in these lipogenic effects. Dose-dependent increases in biliary cholesterol and decreases in phospholipid and bile acid occurred in BMS-779788-treated animals, similar to LXR agonist effects reported in mouse. In summary, BMS- 779788, a partial LXRβ selective agonist, has decreased lipogenic potential compared with a full pan agonist in cynomolgus monkeys, with similar potency in the induction of genes known to stimulate RCT. This provides support in nonhuman primates for improving LXR agonist therapeutic windows by limiting LXRα activity.
- 189Wrobel, J.; Steffan, R.; Bowen, S. M.; Magolda, R.; Matelan, E.; Unwalla, R.; Basso, M.; Clerin, V.; Gardell, S. J.; Nambi, P.; Quinet, E.; Reminick, J. I.; Vlasuk, G. P.; Wang, S.; Feingold, I.; Huselton, C.; Bonn, T.; Farnegardh, M.; Hansson, T.; Nilsson, A. G.; Wilhelmsson, A.; Zamaratski, E.; Evans, M. J. Indazole-Based Liver X Receptor (LXR) Modulators with Maintained Atherosclerotic Lesion Reduction Activity but Diminished Stimulation of Hepatic Triglyceride Synthesis. J. Med. Chem. 2008, 51 (22), 7161– 7168, DOI: 10.1021/jm800799q[ACS Full Text], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlWqur7J&md5=8a9e70594fc1f4f3c32bc2e3cd040248Indazole-Based Liver X Receptor (LXR) Modulators with Maintained Atherosclerotic Lesion Reduction Activity but Diminished Stimulation of Hepatic Triglyceride SynthesisWrobel, Jay; Steffan, Robert; Bowen, S. Marc; Magolda, Ronald; Matelan, Edward; Unwalla, Rayomand; Basso, Michael; Clerin, Valerie; Gardell, Stephen J.; Nambi, Ponnal; Quinet, Elaine; Reminick, Jason I.; Vlasuk, George P.; Wang, Shuguang; Feingold, Irene; Huselton, Christine; Bonn, Tomas; Farnegardh, Mathias; Hansson, Tomas; Nilsson, Annika Goos; Wilhelmsson, Anna; Zamaratski, Edouard; Evans, Mark J.Journal of Medicinal Chemistry (2008), 51 (22), 7161-7168CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepd. as LXR modulators. These compds. were partial agonists in transactivation assays when compared to T0901317 and were slightly weaker with respect to potency and efficacy on LXRα than on LXRβ. Lead compds. in this series WAY-252623 (I) and WAY-214950 (II) showed less lipid accumulation in HepG2 cells than potent full agonists T0901317 and WAY-254011, but were comparable in efficacy to T0901317 and WAY-254011 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. WAY-214950 reduced aortic lesion area in LDLR knockout mice equivalently to WAY-254011, or pos. control GW3965. In a 7-day hamster model, WAY-214950 showed a lesser propensity for plasma TG elevation than WAY-254011,, when the compds. were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for GW3965, the lack of TG effect of WAY-214950 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by WAY-254011. These results suggest indazoles such as WAY-214950 may have an improved profile for potential use as a therapeutic agent.
- 190Stachel, S. J.; Zerbinatti, C.; Rudd, M. T.; Cosden, M.; Suon, S.; Nanda, K. K.; Wessner, K.; Dimuzio, J.; Maxwell, J.; Wu, Z.; Uslaner, J. M.; Michener, M. S.; Szczerba, P.; Brnardic, E.; Rada, V.; Kim, Y.; Meissner, R.; Wuelfing, P.; Yuan, Y.; Ballard, J.; Holahan, M.; Klein, D. J.; Lu, J.; Fradera, X.; Parthasarathy, G.; Uebele, V. N.; Chen, Z.; Li, Y.; Li, J.; Cooke, A. J.; Bennett, D. J.; Bilodeau, M. T.; Renger, J. Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease. J. Med. Chem. 2016, 59 (7), 3489– 3498, DOI: 10.1021/acs.jmedchem.6b00176[ACS Full Text], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XkvVaht7k%253D&md5=17ebde13cff428dffe1b7ef70944ee28Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer's DiseaseStachel, Shawn J.; Zerbinatti, Celina; Rudd, Michael T.; Cosden, Mali; Suon, Sokreine; Nanda, Kausik K.; Wessner, Keith; DiMuzio, Jillian; Maxwell, Jill; Wu, Zhenhua; Uslaner, Jason M.; Michener, Maria S.; Szczerba, Peter; Brnardic, Edward; Rada, Vanessa; Kim, Yuntae; Meissner, Robert; Wuelfing, Peter; Yuan, Yang; Ballard, Jeanine; Holahan, Marie; Klein, Daniel J.; Lu, Jun; Fradera, Xavier; Parthasarathy, Gopal; Uebele, Victor N.; Chen, Zhongguo; Li, Yingjie; Li, Jian; Cooke, Andrew J.; Bennett, D. Jonathan; Bilodeau, Mark T.; Renger, JohnJournal of Medicinal Chemistry (2016), 59 (7), 3489-3498CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, soly., and phys. properties to allow efficacy and safety studies in vivo. Compd. 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.
- 191Gezen-Ak, D.; Dursun, E. Molecular Basis of Vitamin D Action in Neurodegeneration: The Story of a Team Perspective. Hormones 2019, 18 (3), 17– 21, DOI: 10.1007/s42000-018-0087-4[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3crlsFGksg%253D%253D&md5=922bd4c7bc56fb90646b6d16e9882e78Molecular basis of vitamin D action in neurodegeneration: the story of a team perspectiveGezen-Ak Duygu; Dursun ErdincHormones (Athens, Greece) (2019), 18 (1), 17-21 ISSN:.Vitamin D, a secosteroid hormone, has, over the years, mainly been known for its classic role in the maintenance of calcium homeostasis of the human body. However, there is increasing understanding that vitamin D contributes to the regulation of Ca(2+) homeostasis, especially via voltage-gated calcium channels, in another major organ that uses calcium, the brain. Almost 30 years ago, the role of dysregulation in the aging brain and in Alzheimer's disease (AD) gave rise to the Ca(2+) hypothesis of brain aging and dementia. We thus made calcium homeostasis the starting point of our studies, proposing the notion that the consequences of long-term deficiency and/or inefficient utilization of vitamin D may cause the disruption of calcium homeostasis in neurons, this creating a vulnerability of neurons to aging and neurodegeneration. In this mini-review, we aim to describe the potential of vitamin D (cholecalciferol) as a neurosteroid based on our findings and conclusions.
- 192Makishima, M.; Lu, T. T.; Xie, W.; Whitfield, G. K.; Domoto, H.; Evans, R. M.; Haussler, M. R.; Mangelsdorf, D. J. Vitamin D Receptor as an Intestinal Bile Acid Sensor. Science 2002, 296 (5571), 1313– 1316, DOI: 10.1126/science.1070477[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xjsl2qur0%253D&md5=39a9632c4acad961660105bf4121bde0Vitamin D receptor as an intestinal bile acid sensorMakishima, Makoto; Lu, Timothy T.; Xie, Wen; Whitfield, G. Kerr; Domoto, Hideharu; Evans, Ronald M.; Haussler, Mark R.; Mangelsdorf, David J.Science (Washington, DC, United States) (2002), 296 (5571), 1313-1316CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The authors show that VDR also functions as a receptor for the secondary bile acid lithocholic acid (LCA), which is hepatotoxic and a potential enteric carcinogen. VDR is an order of magnitude more sensitive to LCA and its metabolites than are other nuclear receptors. Activation of VDR by LCA or vitamin D induced expression in vivo of CYP3A, a cytochrome P 450 enzyme that detoxifies LCA in the liver and intestine. These studies offer a mechanism that may explain the proposed protective effects of vitamin D and its receptor against colon cancer.
- 193Yao, B.; He, J.; Yin, X.; Shi, Y.; Wan, J.; Tian, Z. The Protective Effect of Lithocholic Acid on the Intestinal Epithelial Barrier Is Mediated by the Vitamin D Receptor via a SIRT1/Nrf2 and NF-KB Dependent Mechanism in Caco-2 Cells. Toxicol. Lett. 2019, 316, 109– 118, DOI: 10.1016/j.toxlet.2019.08.024[Crossref], [PubMed], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVSqsrzF&md5=c08df1d014dbf00b083c41a937bf5838The protective effect of lithocholic acid on the intestinal epithelial barrier is mediated by the vitamin D receptor via a SIRT1/Nrf2 and NF-κB dependent mechanism in Caco-2 cellsYao, Baiyu; He, Jingni; Yin, Xin; Shi, Yang; Wan, Jun; Tian, ZhongToxicology Letters (2019), 316 (), 109-118CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Lithocholic acid (LCA) is both a secondary bile acid and a vitamin D receptor (VDR) ligand. The VDR is activated by 1,25-dihydroxy vitamin D3 and plays an important role in maintaining integrity of the intestinal mucosal barrier. LCA can also substitute for vitamin D to carry out the in vivo functions of vitamin D. However, it is unclear whether activation of the VDR by LCA affects mucosal barrier function. In the present study, the authors researched the protective effect of LCA on tumor necrosis factor-alpha (TNF-α)-induced intestinal epithelial barrier dysfunction in Caco-2 cells of the human epithelial intestinal adenocarcinoma cell line. Caco-2 cell monolayers were pretreated with LCA and then exposed to 100 ng/mL TNF-α. The results showed that LCA alleviated the decrease in transepithelial elec. resistance and the increase in FITC-Dextran flux induced by TNF-α. LCA ameliorated the TNF-α-induced decrease in protein expression and distribution of ZO-1, E-cadherin, Occludin, and Claudin-1, which are tight junction markers. Addnl., the LCA treatment effectively counteracted TNF-α-mediated downregulation of silent information regulator 1 (SIRT1), nuclear factor erythroid-2-related factor 2 (Nrf2), and heme oxygenase-1, which are related to oxidative stress. Increases in NF-κB p-p65 and p-IκB-α induced by TNF-α were significantly inhibited by LCA. Considering all these, the present study indicates that LCA has a significant protective effect on TNF-α-induced injury of intestinal barrier function through the VDR and suggests that suppressing NF-κB signaling and activating the SIRT1/Nrf2 pathway might be one of the mechanisms underlying the protective effect of LCA.
- 194Eyles, D. W.; Smith, S.; Kinobe, R.; Hewison, M.; McGrath, J. J. Distribution of the Vitamin D Receptor and 1α-Hydroxylase in Human Brain. J. Chem. Neuroanat. 2005, 29 (1), 21– 30, DOI: 10.1016/j.jchemneu.2004.08.006[Crossref], [PubMed], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVKktrrI&md5=f1117120c82d61138b44eed5b4dce0d7Distribution of the vitamin D receptor and 1α-hydroxylase in human brainEyles, Darryl W.; Smith, Steven; Kinobe, Robert; Hewison, Martin; McGrath, John J.Journal of Chemical Neuroanatomy (2005), 29 (1), 21-30CODEN: JCNAEE; ISSN:0891-0618. (Elsevier B.V.)Despite a growing body of evidence that Vitamin D is involved in mammalian brain functioning, there has been a lack of direct evidence about its role in the human brain. This paper reports, for the first time, the distribution of the 1,25-dihydroxyvitamin D3 receptor (VDR), and 1α-hydroxylase (1α-OHase), the enzyme responsible for the formation of the active vitamin in the human brain. The receptor and the enzyme were found in both neurons and glial cells in a regional and layer-specific pattern. The VDR was restricted to the nucleus while 1α-OHase was distributed throughout the cytoplasm. The distribution of the VDR in human brain was strikingly similar to that reported in rodents. Many regions contained equiv. amts. of both the VDR and 1α-OHase, however the macrocellular cells within the nucleus basalis of Meynert (NBM) and the Purkinje cells in the cerebellum expressed 1α-OHase in the absence of VDR. The strongest immunohistochem. staining for both the receptor and enzyme was in the hypothalamus and in the large (presumably dopaminergic) neurons within the substantia nigra. The obsd. distribution of the VDR is consistent with the proposal that Vitamin D operates in a similar fashion to the known neurosteroids. The widespread distribution of 1α-OHase and the VDR suggests that Vitamin D may have autocrine/paracrine properties in the human brain.
- 195Burne, T. H. J.; McGrath, J. J.; Eyles, D. W.; Mackay-Sim, A. Behavioural Characterization of Vitamin D Receptor Knockout Mice. Behav. Brain Res. 2005, 157 (2), 299– 308, DOI: 10.1016/j.bbr.2004.07.008[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXisl2ntA%253D%253D&md5=e1f749cdaf7fc87f63411903b246d5beBehavioural characterization of Vitamin D receptor knockout miceBurne, Thomas H. J.; McGrath, John J.; Eyles, Darryl W.; Mackay-Sim, AlanBehavioural Brain Research (2005), 157 (2), 299-308CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)Vitamin D (calcitriol) is a nuclear transcription regulator acting via a nuclear hormone receptor (VDR). In addn. to its role in the regulation of calcium and phosphate homeostasis and in bone formation, Vitamin D is also thought to be involved in brain function. The aim of this study was to behaviorally phenotype VDR knockout mice. We characterized the behavior of VDR null mutant mice and wildtype littermate controls by subjecting them to a range of tests including a primary behavioral screen (using the SHIRPA protocol), rotarod, gait anal., Y-maze, marble burying test, bedding test, holeboard test, elevated plus maze, open field test and prepulse inhibition of the acoustic startle response. There were no effects of genotype on most of the scores from the SHIRPA protocol except that VDR -/- mice had alopecia, were shorter and weighed less than VDR +/+ mice. VDR -/- mice had a shorter gait as well as impairments on the rotarod, in the bedding test and impaired habituation in both the open field and on the acoustic startle response. The VDR -/- mice had normal acoustic startle responses but had impaired PPI at long (256 ms) but not short (64 ms) prepulse to pulse intervals. The VDR -/- mice were less active in the open field and buried fewer marbles in the marble burying test. However, there were no differences in the time spent on the open arms of the elevated plus maze or in working memory as assessed by repeat arm entries on the Y-maze. Therefore, it appears that VDR -/- mice have muscular and motor impairments that significantly affects locomotor behavior but seemingly no impairments in cognition as indicated by exploration, working memory or anxiety.
- 196Beecham, G. W.; Martin, E. R.; Li, Y. J.; Slifer, M. A.; Gilbert, J. R.; Haines, J. L.; Pericak-Vance, M. A. Genome-Wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease. Am. J. Hum. Genet. 2009, 84 (1), 35– 43, DOI: 10.1016/j.ajhg.2008.12.008[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpsFakug%253D%253D&md5=3921f86f883e036ef5fae49c45f8ea79Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer diseaseBeecham, Gary W.; Martin, Eden R.; Li, Yi-Ju; Slifer, Michael A.; Gilbert, John R.; Haines, Jonathan L.; Pericak-Vance, Margaret A.American Journal of Human Genetics (2009), 84 (1), 35-43CODEN: AJHGAG; ISSN:0002-9297. (Cell Press)Only Apolipoprotein E polymorphisms have been consistently assocd. with the risk of late-onset Alzheimer disease (LOAD), but they represent only a minority of the underlying genetic effect. To identify addnl. LOAD risk loci, we performed a genome-wide assocn. study (GWAS) on 492 LOAD cases and 498 cognitive controls using Illumina's HumanHap550 beadchip. An addnl. 238 cases and 220 controls were used as a validation data set for single-nucleotide polymorphisms (SNPs) that met genome-wide significance. To validate addnl. assocd. SNPs and nominally assocd. candidate genes, we imputed SNPs from our GWAS using a previously published LOAD GWAS1 and the IMPUTE program. Assocn. testing was performed with the Cochran-Armitage trend test and logistic regression, and genome-wide significance was detd. with the False Discovery Rate-Beta Uniform Mixt. method. Extensive quality-control methods were performed at both the sample and the SNP level. The GWAS confirmed the known APOE assocn. and identified assocn. with a 12q13 locus at genome-wide significance; the 12q13 locus was confirmed in our validation data set. Four addnl. highly assocd. signals (1q42, 4q28, 6q14, 19q13) were replicated with the use of the imputed data set, and six candidate genes had SNPs with nominal assocn. in both the GWAS and the joint imputated data set. These results help to further define the genetic architecture of LOAD.
- 197Butler, M. W.; Burt, A.; Edwards, T. L.; Zuchner, S.; Scott, W. K.; Martin, E. R.; Vance, J. M.; Wang, L. Vitamin D Receptor Gene as a Candidate Gene for Parkinson Disease. Ann. Hum. Genet. 2011, 75 (2), 201– 210, DOI: 10.1111/j.1469-1809.2010.00631.x[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjvFOgtbo%253D&md5=8e97d45c5e8eb65878abe41af5b08fa7Vitamin D receptor gene as a candidate gene for Parkinson diseaseButler, Megan W.; Burt, Amber; Edwards, Todd L.; Zuchner, Stephan; Scott, William K.; Martin, Eden R.; Vance, Jeffery M.; Wang, LiyongAnnals of Human Genetics (2011), 75 (2), 201-210CODEN: ANHGAA; ISSN:0003-4800. (Wiley-Blackwell)Vitamin D and vitamin D receptor (VDR) have been postulated as environmental and genetic factors in neurodegeneration disorders including multiple sclerosis (MS), Alzheimer disease (AD), and recently Parkinson disease (PD). Given the sparse data on PD, we conducted a two-stage study to evaluate the genetic effects of VDR in PD. In the discovery stage, 30 tagSNPs in VDR were tested for assocn. with risk as a discrete trait and age-at-onset (AAO) as a quant. trait in 770 Caucasian PD families. In the validation stage, 18 VDR SNPs were tested in an independent Caucasian cohort (267 cases and 267 controls) constructed from a genome-wide assocn. study (GWAS). In the discovery dataset, SNPs in the 5' end of VDR were assocd. with both risk and AAO with more significant evidence of assocn. with AAO (P = 0.0008-0.02). These 5' SNPs were also assocd. with AD in another study. In the validation dataset, SNPs in the 3' end of VDR were assocd. with AAO (P = 0.003) but not risk. The 3' end SNP has been assocd. with both MS and AD in previous studies. Our findings suggest VDR as a potential susceptibility gene and support an essential role of vitamin D in PD.
- 198Kim, J.-S.; Kim, Y.-I.; Song, C.; Yoon, I.; Park, J.-W.; Choi, Y.-B.; Kim, H.-T.; Lee, K.-S. Association of Vitamin D Receptor Gene Polymorphism and Parkinson’s Disease in Koreans. J. Korean Med. Sci. 2005, 20 (3), 495– 498, DOI: 10.3346/jkms.2005.20.3.495[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXms1eiurY%253D&md5=bd63d3d4a6729edfe07e07ebab85f3b1Association of vitamin D receptor gene polymorphism and parkinson's disease in KoreansKim, Joong-Seok; Kim, Yeong-In; Song, Christopher; Yoon, Injin; Park, Jeong-Wook; Choi, Young-Bin; Kim, Hee-Tae; Lee, Kwang-SooJournal of Korean Medical Science (2005), 20 (3), 495-498CODEN: JKMSEH; ISSN:1011-8934. (Korean Academy of Medical Science)1 α,25-Dihydroxyvitamin D3 (1,25(OH)2D3), which is the biol. active form of vitamin D, has anti-inflammatory effects and can prevent exptl. Parkinson's disease (PD). 1,25(OH)2D3 exerts most of its actions only after it binds to its specific nuclear receptors. Eighty-five Korean patients with PD and 231 unrelated healthy individuals were evaluated to det. if vitamin D receptor gene (VDRG) Bsml polymorphisms were markers for the susceptibility to PD in Korean patients. Each polymorphism was detected using polymerase chain reaction (PCR)-based restriction anal. In addn., the relationship between the Bsml polymorphisms and the clin. manifestations of PD was evaluated. Overexpression of the b allele (91.2 vs. 85.7%; p=0.069) and homozygote bb (84.7 vs. 72.7%; p=0.043) was found in the PD patients compared with the controls. These results show for the first time an assocn. between PD and a VDRG polymorphism, which might be involved in the pathogenesis of PD, or in the linkage disequil. of the VDRG to another pathogenic gene locus.
- 199Niino, M.; Miyazaki, Y. Genetic Polymorphisms Related to Vitamin D and the Therapeutic Potential of Vitamin D in Multiple Sclerosis. Can. J. Physiol. Pharmacol. 2015, 93 (5), 319– 325, DOI: 10.1139/cjpp-2014-0374[Crossref], [PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltVSis74%253D&md5=ca1410da20829884650b88cabdaa6f7eGenetic polymorphisms related to vitamin D and the therapeutic potential of vitamin D in multiple sclerosis1Niino, Masaaki; Miyazaki, YuseiCanadian Journal of Physiology and Pharmacology (2015), 93 (5), 319-325CODEN: CJPPA3; ISSN:0008-4212. (Canadian Science Publishing)Vitamin D receptors (VDRs), which are responsible for most vitamin D functions, are expressed on various immune cells. Vitamin D is considered to be a potent immunomodulator. A variety of cells in the central nervous system (CNS) also express VDRs; thus, vitamin D may play a role in the regulation of neurodegeneration and repair processes within the CNS. Considered together with epidemiol. studies, low vitamin D status is reckoned to be one of the risk factors for multiple sclerosis (MS). Further, vitamin D is considered to be a possible treatment for MS. However, previous clin. trials with small cohorts have not demonstrated significant effects of vitamin D in MS. Current ongoing clin. trials with large cohorts could provide answers with respect to the clin. effects of vitamin D in MS. However, genetic studies have suggested that genes assocd. with vitamin D, including VDRs, are susceptible genes for MS. Vitamin D needs to be considered from the perspective of the interaction between vitamin-D-related genetic factors and environmental factors affecting vitamin D levels.
- 200Vinh quôc Luong, K.; Thi Hoàng Nguyên, L. Vitamin D and Parkinson’s Disease. J. Neurosci Res. 2012, 90, 2227– 2236, DOI: 10.1002/jnr.23115[Crossref], [PubMed], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bitFWhug%253D%253D&md5=df1252abf63c4dfa79271195cc633a71Vitamin D and Parkinson's diseaseVinh Quoc Luong Khanh; Thi Hoang Nguyen LanJournal of neuroscience research (2012), 90 (12), 2227-36 ISSN:.Parkinson's disease (PD) is the second most common form of neurodegeneration among the elderly population. PD is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. Interestingly, a significant association has been demonstrated between PD and low levels of vitamin D in the serum, and vitamin D supplement appears to have a beneficial clinical effect on PD. Genetic studies have provided the opportunity to determine which proteins link vitamin D to PD pathology, e.g., Nurr1 gene, toll-like receptor, gene related to lipid disorders, vascular endothelial factor, tyrosine hydroxylase, and angiogenin. Vitamin D also exerts its effects on cancer through nongenomic factors, e.g., bacillus Calmette-Guerin vaccination, interleukin-10, Wntβ-catenin signaling pathways, mitogen-activated protein kinase pathways, and the reduced form of the nicotinamide adenine dinucleotide phosphate. In conclusion, vitamin D might have a beneficial role in PD. Calcitriol is best used for PD because it is the active form of the vitamin D(3) metabolite and modulates inflammatory cytokine expression. Further investigation with calcitriol in PD is needed.
- 201Banerjee, A.; Khemka, V. K.; Ganguly, A.; Roy, D.; Ganguly, U.; Chakrabarti, S. Vitamin D and Alzheimer’s Disease: Neurocognition to Therapeutics. Int. J. Alzheimer's Dis. 2015, 2015, 192747, DOI: 10.1155/2015/192747[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC283gs12jsQ%253D%253D&md5=a367406ad5891beb4a343b2bdb58ad06Vitamin D and Alzheimer's Disease: Neurocognition to TherapeuticsBanerjee Anindita; Khemka Vineet Kumar; Ganguly Anirban; Roy Debashree; Ganguly Upasana; Chakrabarti SasankaInternational journal of Alzheimer's disease (2015), 2015 (), 192747 ISSN:2090-8024.Alzheimer's disease (AD), the major cause of dementia worldwide, is characterized by progressive loss of memory and cognition. The sporadic form of AD accounts for nearly 90% of the patients developing this disease. The last century has witnessed significant research to identify various mechanisms and risk factors contributing to the complex etiopathogenesis of AD by analyzing postmortem AD brains and experimenting with animal and cell culture based models. However, the treatment strategies, as of now, are only symptomatic. Accumulating evidences suggested a significant association between vitamin D deficiency, dementia, and AD. This review encompasses the beneficial role of vitamin D in neurocognition and optimal brain health along with epidemiological evidence of the high prevalence of hypovitaminosis D among aged and AD population. Moreover, disrupted signaling, altered utilization of vitamin D, and polymorphisms of several related genes including vitamin D receptor (VDR) also predispose to AD or AD-like neurodegeneration. This review explores the relationship between this gene-environmental influence and long term vitamin D deficiency as a risk factor for development of sporadic AD along with the role and rationale of therapeutic trials with vitamin D. It is, therefore, urgently warranted to further establish the role of this potentially neuroprotective vitamin in preventing and halting progressive neurodegeneration in AD patients.
- 202Luong, K.; Nguyen, L. Role of Vitamin D in Parkinson’s Disease. ISRN Neurol. 2012, 2012, 134289 DOI: 10.5402/2012/134289
- 203Munger, K. L.; Levin, L. I.; Hollis, B. W.; Howard, N. S.; Ascherio, A. Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis. J. Am. Med. Assoc. 2006, 296 (23), 2832– 2838, DOI: 10.1001/jama.296.23.2832[Crossref], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtlCqtL3J&md5=af7a4ba3d8bb7d69375933655f575179Serum 25-hydroxyvitamin D levels and risk of multiple sclerosisMunger, Kassandra L.; Levin, Lynn I.; Hollis, Bruce W.; Howard, Noel S.; Ascherio, AlbertoJAMA, the Journal of the American Medical Association (2006), 296 (23), 2832-2838CODEN: JAMAAP; ISSN:0098-7484. (American Medical Association)Context Epidemiol. and exptl. evidence suggests that high levels of vitamin D, a potent immuno-modulator, may decrease the risk of multiple sclerosis. There are no prospective studies addressing this hypothesis. Objective To examine whether levels of 25-hydroxyvitamin D are assocd. with risk of multiple sclerosis. Design, Setting, and Participants Prospective, nested case-control study among more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. Multiple sclerosis cases were identified through Army and Navy phys. disability databases for 1992 through 2004, and diagnoses were confirmed by medical record review. Each case (n = 257) was matched to 2 controls by age, sex, race/ethnicity, and dates of blood collection. Vitamin D status was estd. by averaging 25-hydroxyvitamin D levels of 2 or more serum samples collected before the date of initial multiple sclerosis symptoms. Main Outcome Measures Odds ratios of multiple sclerosis assocd. with continuous or categorical levels (quantiles or a priori-defined categories) of serum 25-hydroxyvitamin D within each racial/ethnic group. Results Among whites (148 cases, 296 controls), the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D (odds ratio [OR] for a 50-nmol/L increase in 25-hydroxyvitamin D, 0.59; 95% confidence interval, 0.36-0.97). In categorical analyses using the lowest quintile (<63.3 nmol/L) as the ref., the ORs for each subsequent quintile were 0.57, 0.57, 0.74, and 0.38 (P =.02 for trend across quintiles). Only the OR for the highest quintile, corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L, was significantly different from 1.00 (OR, 0.38; 95% confidence interval, 0.19-0.75; P =.006). The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years. Among blacks and Hispanics (109 cases, 218 controls), who had lower 25-hydroxyvitamin D levels than whites, no significant assocns. between vitamin D and multiple sclerosis risk were found. Conclusion The results of our study suggest that high circulating levels of vitamin D are assocd. with a lower risk of multiple sclerosis.
- 204Moretti, R.; Morelli, M. E.; Caruso, P. Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact. Int. J. Mol. Sci. 2018, 19 (8), 2245, DOI: 10.3390/ijms19082245[Crossref], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXns1Wju7o%253D&md5=7c20b0c642d3fb41bd1b5785093be3dcVitamin D in neurological diseases: a rationale for a pathogenic impactMoretti, Rita; Morelli, Maria Elisa; Caruso, PaolaInternational Journal of Molecular Sciences (2018), 19 (8), 2245/1-2245/27CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. It is widely known that vitamin D receptors have been found in neurons and glial cells, and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical gray nuclei, and substantia nigra. Vitamin D helps the regulation of neurotrophin, neural differentiation, and maturation, through the control operation of growing factors synthesis (i.e., neural growth factor [NGF] and glial cell line-derived growth factor (GDNF), the trafficking of the septohippocampal pathway, and the control of the synthesis process of different neuromodulators (such as acetylcholine [Ach], dopamine [DA], and gamma-aminobutyric [GABA]). Based on these assumptions, we have written this review to summarize the potential role of vitamin D in neurol. pathologies. This work could be titanic and the results might have been very fuzzy and even incoherent had we not conjectured to taper our first intentions and devoted our interests towards three mainstreams, demyelinating pathologies, vascular syndromes, and neurodegeneration. As a result of the lack of useful therapeutic options, apart from the disease-modifying strategies, the role of different risk factors should be investigated in neurol., as their correction may lead to the improvement of the cerebral conditions. We have explored the relationships between the gene-environmental influence and long-term vitamin D deficiency, as a risk factor for the development of different types of neurol. disorders, along with the role and the rationale of therapeutic trials with vitamin D implementation.
- 205Salzer, J.; Hallmans, G.; Nyström, M.; Stenlund, H.; Wadell, G.; Sundström, P. Vitamin D as a Protective Factor in Multiple Sclerosis. Neurology 2012, 79 (21), 2140– 2145, DOI: 10.1212/WNL.0b013e3182752ea8[Crossref], [PubMed], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslaitbrN&md5=accb50f9e6299dc50dae9298bd4720a3Vitamin D as a protective factor in multiple sclerosisSalzer, Jonatan; Hallmans, Goeran; Nystroem, Maria; Stenlund, Hans; Wadell, Goeran; Sundstroem, PeterNeurology (2012), 79 (21), 2140-2145CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: To examine the assocn. between 25-hydroxyvitamin D (25[OH]D) levels and the risk of multiple sclerosis (MS) in blood samples collected prospectively and during gestation. Methods: In this nested case-control study, 2 population-based biobanks with 291,500 samples from 164,000 persons collected since 1975 in the northern half of Sweden were used. We identified prospectively collected blood samples from MS cases (n = 192, controls matched 2:1) and gestational samples from pregnant mothers where the offspring had later developed MS (n = 37, control mothers matched 5:1). 25(OH)D levels were measured using an ELISA, and the risk of MS was analyzed using matched logistic regression. Results: Levels of 25(OH)D ≥75 (vs <75) nmol/L in prospectively collected blood samples were assocd. with a decreased risk of MS (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.16-0.98). No decrease in MS risk was found in the offspring exposed to gestational 25(OH)D levels ≥75 (vs <75) nmol/L (OR 1.8, 95% CI 0.53-5.8). The prevalence of 25(OH)D levels ≥75 nmol/L in female controls decreased gradually during 1976-2005 (p trend = 0.005). Conclusion: This study supports the presence of an assocn. between high 25(OH)D levels during the years preceding disease onset and a decreased risk of MS. In the very limited material with samples drawn in early pregnancy, where month-of-birth effects were controlled for, we found no assocn. between gestational 25(OH)D levels and MS risk in the offspring. Decreasing 25(OH)D levels in the population may contribute to explain the increasing MS incidence that is suggested from epidemiol. studies.
- 206Grimm, M. O. W.; Lauer, A. A.; Grösgen, S.; Thiel, A.; Lehmann, J.; Winkler, J.; Janitschke, D.; Herr, C.; Beisswenger, C.; Bals, R.; Grimm, H. S.; Hartmann, T. Profiling of Alzheimer’s Disease Related Genes in Mild to Moderate Vitamin D Hypovitaminosis. J. Nutr. Biochem. 2019, 67, 123– 137, DOI: 10.1016/j.jnutbio.2019.01.015[Crossref], [PubMed], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXltFGgtbc%253D&md5=de88609a5533e6d95e9d87122cde0e4fProfiling of Alzheimer's disease related genes in mild to moderate vitamin D hypovitaminosisGrimm, Marcus O. W.; Lauer, Anna A.; Groesgen, Sven; Thiel, Andrea; Lehmann, Johannes; Winkler, Jakob; Janitschke, Daniel; Herr, Christian; Beisswenger, Christoph; Bals, Robert; Grimm, Heike S.; Hartmann, TobiasJournal of Nutritional Biochemistry (2019), 67 (), 123-137CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)A vast majority of the elderly population shows a mild to moderate vitamin D deficiency. Besides the well-known function of vitamin D, vitamin D receptor is also expressed in brain and is discussed to regulate several genes. However very little is known whether genes are regulated, assocd. with Alzheimer's disease (AD). Here we investigate 117 genes, known to be affected in AD, in mouse brain samples with a mild vitamin D hypovitaminosis comparable to the vitamin D status of the elderly population (20%-30% deficiency). The 117 genes include two pos. controls, Nep and Park7, already known to be affected by both AD and vitamin D hypovitaminosis. The 25 most promising candidates were verified in a second independent mouse cohort, resulting in eleven genes further evaluated against three addnl. housekeeping genes. Three of the remaining eight significantly altered genes are involved in APP homeostasis (Snca, Nep, Psmb5), and each one gene in oxidative stress (Park7), inflammation (Casp4), lipid metab. (Abca1), signal transduction (Gnb5) and neurogenesis (Plat). Our results tighten the link of vitamin D and AD and underline that vitamin D influences several genes also in brain, highlighting that a strong link not only to AD but also to other neurodegenerative diseases might exist.
- 207Uberti, F.; Morsanuto, V.; Bardelli, C.; Molinari, C. Protective Effects of 1α,25-Dihydroxyvitamin D3 on Cultured Neural Cells Exposed to Catalytic Iron. Physiol. Rep. 2016, 4 (11), e12769, DOI: 10.14814/phy2.12769
- 208Ibi, M.; Sawada, H.; Nakanishi, M.; Kume, T.; Katsuki, H.; Kaneko, S.; Shimohama, S.; Akaike, A. Protective Effects of 1α,25-(OH)2D3 against the Neurotoxicity of Glutamate and Reactive Oxygen Species in Mesencephalic Culture. Neuropharmacology 2001, 40 (6), 761– 771, DOI: 10.1016/S0028-3908(01)00009-0[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjtleqtL0%253D&md5=aa63e7fb5e85e532aff42c09a5e5656fProtective effects of 1α,25-(OH)2D3 against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic cultureIbi, M.; Sawada, H.; Nakanishi, M.; Kume, T.; Katsuki, H.; Kaneko, S.; Shimohama, S.; Akaike, A.Neuropharmacology (2001), 40 (6), 761-771CODEN: NEPHBW; ISSN:0028-3908. (Elsevier Science Ltd.)This study was undertaken to det. whether 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2D3], an active metabolite of vitamin D, protects dopaminergic neurons against the neurotoxic effects of glutamate and dopaminergic toxins using rat mesencephalic culture. Brief glutamate exposure elicited cytotoxicity in both dopaminergic and non-dopaminergic neurons. Pretreatment, but not co-administration, of 1α,25-(OH)2D3 protected both types of neurons against the cytotoxicity of glutamate in a concn.- and time-dependent manner. The neuroprotective effect of 1α,25-(OH)2D3 was inhibited by the protein synthesis inhibitor, cycloheximide. To investigate the mechanisms of these neuroprotective effects, the authors examd. the effects of 1α,25-(OH)2D3 on neurotoxicity induced by calcium ionophore and reactive oxygen species (ROS). Pretreatment with 1α,25-(OH)2D3 protected both types of neurons against the cytotoxicity induced by A23187 in a concn.-dependent manner. Furthermore, 24-h pretreatment with 1α,25-(OH)2D3 concn.-dependently protected both types of neurons from ROS-induced cytotoxicity. A 24-h incubation with 1α,25-(OH)2D3 inhibited the increase in intracellular ROS level following H2O2 exposure. A 24-h exposure to 1-methyl-4-phenylpyridium ion (MPP+) or 6-hydroxydopamine (6-OHDA) exerted selective neurotoxicity on dopaminergic neurons, and these neurotoxic effects were ameliorated by 1α,25-(OH)2D3. These results suggest that 1α,25-(OH)2D3 provides protection of dopaminergic neurons against cytotoxicity induced by glutamate and dopaminergic toxins by facilitating cellular functions that reduce oxidative stress.
- 209Zhang, D.; Li, M.; Dong, Y.; Zhang, X.; Liu, X.; Chen, Z.; Zhu, Y.; Wang, H.; Liu, X.; Zhu, J.; Shen, Y.; Korner, H.; Ying, S.; Fang, S.; Shen, Y. 1α,25-Dihydroxyvitamin D3 up-Regulates IL-34 Expression in SH-SY5Y Neural Cells. Innate Immun. 2017, 23 (7), 584– 591, DOI: 10.1177/1753425917725391[Crossref], [PubMed], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFGls7vM&md5=9313138b57a98984dca0e89483b6b76f1α,25-Dihydroxyvitamin D3 up-regulates IL-34 expression in SH-SY5Y neural cellsZhang, Dong; Li, Miaomiao; Dong, Yang; Zhang, Xinhui; Liu, Xingyun; Chen, Zhangming; Zhu, Yongji; Wang, Huiming; Liu, Xuwen; Zhu, Jialiang; Shen, Yujun; Korner, Heinrich; Ying, Songcheng; Fang, Shengyun; Shen, YuxianInnate Immunity (2017), 23 (7), 584-591CODEN: IINMCB; ISSN:1753-4259. (Sage Publications Ltd.)Vitamin D supplementation is regarded as a novel approach to treat Alzheimer's disease, but the underlying mechanism remains elusive. The cytokine IL-34 provides strong neuroprotective and survival signals in brain injury and neurodegeneration and could be an immunol. mediator for the vitamin D-induced protection. The aim of this study was to investigate whether human IL-34 is up-regulated in neuronal cells by the hormonally active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3]. We found that IL-34 was detectable in a variety of cell lines and its expression was strongly induced in SH-SY5Y neural cells in a dose- and time-dependent manner by 1α,25(OH)2D3 through the vitamin D receptor (VDR). Furthermore, we identified the core promoter of IL-34 gene and a VDR binding site (CGCCCT) that was required for 1α,25(OH)2D3-induced IL-34 expression. These findings suggest that the induction of IL-34 expression by 1α,25(OH)2D3 may constitute a mechanism that explains the protective function of vitamin D in Alzheimer's disease.
- 210Jiao, K.-P.; Li, S.-M.; Lv, W.-Y.; Jv, M.-L.; He, H.-Y. Vitamin D3 Repressed Astrocyte Activation Following Lipopolysaccharide Stimulation in Vitro and in Neonatal Rats. NeuroReport 2017, 28 (9), 492– 497, DOI: 10.1097/WNR.0000000000000782[Crossref], [PubMed], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnsFehsL8%253D&md5=519557ce6d76a0b6967f43acff03a170Vitamin D3 repressed astrocyte activation following lipopolysaccharide stimulation in vitro and in neonatal ratsJiao, Ke-Ping; Li, Shao-Min; Lv, Wen-Yan; Jv, Ming-Liang; He, Hai-YanNeuroReport (2017), 28 (9), 492-497CODEN: NERPEZ; ISSN:0959-4965. (Lippincott Williams & Wilkins)Vitamin D3 has been reported to be an immunity modulator and high levels of vitamin D3 are correlated with a decreased risk for developing diseases in the central nervous system. Astrocytes are important immune cells and contribute toward inflammation during neurol. diseases. The vitamin D receptor has been reported to be expressed in astrocytes; however, the effect of vitamin D3 on astrocyte activation has not been studied. Here, we found that lipopolysaccharide stimulation in astrocytes could enhance the expression of vitamin D receptor and Cyp27B1, which encodes the enzyme for converting vitamin D3 into its active form. Vitamin D3 suppressed the expression of proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, vascular endothelial growth factor, and also TLR4 in activated astrocytes. Astrocyte activation was further found to be suppressed after the administration of vitamin D3 in neonatal rats injected with lipopolysaccharide in vivo. We demonstrated the antiactivation effect of vitamin D3 in astrocytes after lipopolysaccharide stimulation. Considering the function of reactive astrocytes in augmenting inflammatory response in neurodegeneration and brain injury, the finding that vitamin D3 administration may inhibit astrocyte activation may be potentially useful for the treatment of central nervous system disorders.
- 211Dursun, E.; Gezen-Ak, D.; Yilmazer, S. A Novel Perspective for Alzheimer’s Disease: Vitamin D Receptor Suppression by Amyloid-β and Preventing the Amyloid-β Induced Alterations by Vitamin D in Cortical Neurons. Journal of Alzheimer’s Disease 2011, 23 (2), 207– 219, DOI: 10.3233/JAD-2010-101377[Crossref], [PubMed], [CAS], Google Scholar211https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1Wjsbs%253D&md5=4fb64de69281683840b3723ce895ccbdA Novel Perspective for Alzheimer's Disease: Vitamin D Receptor Suppression by Amyloid-β and Preventing the Amyloid-β Induced Alterations by Vitamin D in Cortical NeuronsDursun, Erdinc; Gezen-Ak, Duygu; Yilmazer, SelmaJournal of Alzheimer's Disease (2011), 23 (2), 207-219CODEN: JADIF9; ISSN:1387-2877. (IOS Press)Amyloid-β (Aβ) is the core component of amyloid plaques of Alzheimer's disease (AD). The effects of Aβ include damage to neuronal plasma membrane, disruption of Ca2+ homeostasis, and alterations of neurotrophic factor levels. The aim of this study was to det. the effects of Aβ treatment on vitamin D receptor (VDR), L-type voltage sensitive calcium channels A1C (LVSCC A1C), NGF, and observing the effects of vitamin D treatment on Aβ induced alterations in primary cortical neurons. As to the latter, we aimed to test the suggested neuroprotective role of vitamin D as a neglected neurosteroid. The expressions of VDR and LVSCC A1C were studied with qRT-PCR and Western blotting. NGF and cytotoxicity levels were detd. by ELISA. Apoptotic cell death was investigated with caspase-3 protein expression by Western blotting. Our results showed that the Aβ triggers neurodegeneration not only by inducing LVSCC A1C expression and NGF levels and but also by dramatically suppressing VDR expression. Administration of vitamin D to this model protected neurons by preventing cytotoxicity and apoptosis, and also by downregulating LVSCC A1C and upregulating VDR. Addnl., vitamin D brought NGF expression to a state of equil. and did not show its apoptosis inducing effects. Consequently, prevention of Aβ toxicity which was one of the major component of AD type pathol. by vitamin D treatment and understanding how Aβ effects vitamin D related pathways, might open up new frontiers in clarifying mol. mechanisms of neurodegeneration and provide basis for novel perspectives in both preventing and treating AD.
- 212Niino, M. Vitamin D and Its Immunoregulatory Role in Multiple Sclerosis. Drugs Today (Barc) 2010, 46 (4), 279– 290, DOI: 10.1358/dot.2010.46.4.1476498[Crossref], [PubMed], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3czmsVGitA%253D%253D&md5=129df007c7385d404b98e45d3b64e116Vitamin D and its immunoregulatory role in multiple sclerosisNiino MasaakiDrugs of today (Barcelona, Spain : 1998) (2010), 46 (4), 279-90 ISSN:1699-3993.Mapping the distribution of multiple sclerosis (MS) reveals a high prevalence of the disease in high-latitude areas, suggesting a positive relationship between vitamin D and MS. Vitamin D is known to play an important role in bone and mineral homeostasis. It has recently been reported that several types of immune cells express vitamin D receptors and that vitamin D has strong immune-modulating effects. Vitamin D and its analogues inhibited experimental autoimmune encephalomyelitis (EAE, an animal model of MS) and there have been reports of small clinical trials on the treatment of MS with vitamin D. Furthermore, there have been discussions on the association between vitamin D levels and MS and about the genetic risk of vitamin D receptor (VDR) gene polymorphisms in MS. The current review discusses the immunological functions of vitamin D, the association between vitamin D and MS and expectations regarding the role of vitamin D in future treatments of MS.
- 213Kim, H.; Shin, J.-Y.; Lee, Y.-S.; Yun, S. P.; Maeng, H.-J.; Lee, Y. Brain Endothelial P-Glycoprotein Level Is Reduced in Parkinson’s Disease via a Vitamin D Receptor-Dependent Pathway. Int. J. Mol. Sci. 2020, 21 (22), 8538, DOI: 10.3390/ijms21228538[Crossref], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFyhu7zI&md5=93f5ee512d5e3e0ccd9540c3d31df6eaBrain endothelial P-glycoprotein level is reduced in Parkinson's disease via a vitamin D receptor-dependent pathwayKim, Hyojung; Shin, Jeong-Yong; Lee, Yun-Song; Yun, Seung Pil; Maeng, Han-Joo; Lee, YunjongInternational Journal of Molecular Sciences (2020), 21 (22), 8538CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)The progressive neurodegeneration in Parkinson's disease (PD) is accompanied by neuroinflammation and endothelial vascular impairment. Although the vitamin D receptor (VDR) is expressed in both dopamine neurons and brain endothelial cells, its role in the regulation of endothelial biol. has not been explored in the context of PD. In a 6-hydroxydopamine (6-OHDA)-induced PD mouse model, we obsd. reduced transcription of the VDR and its downstream target genes, CYP24 and MDR1a. The 6-OHDA-induced transcriptional repression of these genes were recovered after the VDR ligand-1α25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment. Similarly, reduced vascular protein expression of P-glycoprotein (P-gp), encoded by MDR1a, after 6-OHDA administration was reversed by 1,25(OH)2D3. Moreover, marked redn. of endothelial P-gp expression with concomitant α-synuclein aggregation was found in a combinatorial AAV-α-Syn/α-Syn preformed fibril (PFF) injection mouse model and postmortem PD brains. Supporting the direct effect of α-synuclein aggregation on endothelial biol., PFF treatment of human umbilical vein endothelial cells (HUVECs) was sufficient to induce α-synuclein aggregation and repress transcription of the VDR. PFF-induced P-gp downregulation and impaired functional activity in HUVECs completely recovered after 1,25(OH)2D3 treatment. Taken together, our results suggest that a dysfunctional VDR-P-gp pathway could be a potential target for the maintenance of vascular homeostasis in PD pathol. conditions.
- 214Maestro, M. A.; Molnár, F.; Carlberg, C. Vitamin D and Its Synthetic Analogs. J. Med. Chem. 2019, 62 (15), 6854– 6875, DOI: 10.1021/acs.jmedchem.9b00208[ACS Full Text], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmtFGmtL8%253D&md5=fe8f12486f400eb3e273b2f505e5cd43Vitamin D and its synthetic analogsMaestro, Miguel A.; Molnar, Ferdinand; Carlberg, CarstenJournal of Medicinal Chemistry (2019), 62 (15), 6854-6875CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. For many individuals, in particular during winter, supplementation with the secosteroid vitamin D3 is essential for the prevention of bone disorders, muscle weakness, autoimmune diseases, and possibly also different types of cancer. Vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as potent agonist of the transcription factor vitamin D receptor (VDR). Thus, vitamin D directly affects chromatin structure and gene regulation at thousands of genomic loci, i.e., the epigenome and transcriptome of its target tissues. Modifications of 1,25(OH)2D3 at its side-chain, A-ring, triene system, or C-ring, alone and in combination, as well as nonsteroidal mimics provided numerous potent VDR agonists and some antagonists. The nearly 150 crystal structures of VDR's ligand-binding domain with various vitamin D compds. allow a detailed mol. understanding of their action. This review discusses the most important vitamin D analogs presented during the past 10 years and mol. insight derived from new structural information on the VDR protein.
- 215Bishop, J. E.; Collins, E. D.; Okamura, W. H.; Norman, A. W. Profile of Ligand Specificity of the Vitamin D Binding Protein for 1α,25-dihydroxyvitamin D3 and Its Analogs. J. Bone Miner. Res. 1994, 9 (8), 1277– 1288, DOI: 10.1002/jbmr.5650090818[Crossref], [PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXns12juw%253D%253D&md5=794df4d261834964fec27e1c0d9c5500Profile of ligand specificity of the vitamin D binding protein for 1α,25-dihydroxyvitamin D3 and its analogsBishop, June E.; Collins, Elaine D.; Okamura, William H.; Norman, Anthony W.Journal of Bone and Mineral Research (1994), 9 (8), 1277-88CODEN: JBMREJ; ISSN:0884-0431.The profile of structural preference for the ligand binding domain of the human vitamin D binding protein (DBP) was detd. by steroid competition assay of 71 analogs of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3]. The following categories of structural modification were evaluated [values represent fold change; R = redn., I = increase in binding to the DBP from the ref. 1α,25(OH)2D3]: (1) deletion in the A ring of the 1α-hydroxyl (20-1600I); (2) conversion of the triene system to the previtamin form (6-40R); (3) addn. of substituents to carbon 11 of the C ring (4-14R); (4) inversion of the C/D ring junction (8-20R); (5) unsatn. of the D ring (16-ene; 4-140R); (6) replacement of hydrogen with deuterium atoms (no effect); alteration of the side chain by (7) adding or deleting carbon atoms (5-12R); (8) addn. of fluorines (0.2-10R); (9) presence of unsatn. (22-ene, 0-5R; 23-ene, 3R-10I; 23-yne, 5-20R); (10) addn. of hydroxyls (2-100R); and (11) addn. of an arom. ring (0-20I). Thus, the DBP ligand binding domain could tolerate only modest changes to the structure of 1α,25(OH)2D3 without a redn. in binding of the analog. The increases in binding seen in the arom. side chain and with a triple bond at carbon-23 may be indicative of a preferred conformation of the flexible 1α,25(OH)2D3 side chain. In addn., a comparison was made of the DBP ligand binding domain with that of the human HL-60 cell 1α,25(OH)2D3 nuclear receptor. Both ligand binding domains could equivalently accommodate to the presence of (1) a side-chain cyclopropyl group, (2) 22-ene or 23-yne, (3) lengthening the side chain by two carbons, (4) presence of four to six fluorine atoms, (5) substitution of an oxygen for carbon 22, and (6) presence of a 22-[m-(dimethylhydroxymethyl)phenyl] arom. group in the side chain. The DPB could tolerate better than the HL-60 cell receptor the presence of a 22-(p-hydroxyphenyl) arom. group in the side chain and the absence of the 1α-hydroxyl. In contrast, the HL-60 cell receptor could tolerate better than the DBP the following structural modifications: presence of a 16-ene, or 16-ene plus 23-yne unsatn., and presence of an 11β-hydroxyl.
- 216Saito, N.; Matsunaga, T.; Saito, H.; Anzai, M.; Takenouchi, K.; Miura, D.; Namekawa, J.; Ishizuka, S.; Kittaka, A. Further Synthetic and Biological Studies on Vitamin D Hormone Antagonists Based on C24-Alkylation and C2α-Functionalization of 25-Dehydro-1α- Hydroxyvitamin D3–26,23-Lactones. J. Med. Chem. 2006, 49 (24), 7063– 7075, DOI: 10.1021/jm060797q[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFKlurbO&md5=f361104793a47a52e79eb358c23f78dbFurther Synthetic and Biological Studies on Vitamin D Hormone Antagonists Based on C24-Alkylation and C2α-Functionalization of 25-Dehydro-1α-hydroxyvitamin D3-26,23-lactonesSaito, Nozomi; Matsunaga, Toshihiro; Saito, Hiroshi; Anzai, Miyuki; Takenouchi, Kazuya; Miura, Daishiro; Namekawa, Jun-ichi; Ishizuka, Seiichi; Kittaka, AtsushiJournal of Medicinal Chemistry (2006), 49 (24), 7063-7075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)An efficient synthesis and the biol. evaluation of 80 novel analogs of 25-dehydro-1α-hydroxyvitamin D3-26,23S-lactone I (TEI-9647) and its 23R epimer in which the lactone ring was systematically functionalized by introduction of a C1 to C4 primary alkyl group at the C24 position (5 sets of 4 diastereomers), together with their C2α-Me, 3-hydroxypropyl, and 3-hydroxypropoxy-substituted derivs. were described. The triene structure of the vitamin D3 was constructed using palladium-catalyzed alkenylative cyclization of the A-ring precursor enyne with the CD-ring counterpart bromoolefin having the C24-alkylated lactone moiety on the side chain. The CD-ring precursors having 23,24-cis lactones were prepd. by using a chromium-mediated syn-selective allylation-lactonization process, and the 23,24-trans lactone derivs. were derived from these via inversion of the C23 stereochem. The biol. evaluation revealed that both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition of vitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length of the primary alkyl group on the lactone ring. Furthermore, the C2α-functionalization of the C24-alkylated vitamin D3 lactones dramatically enhanced their biol. activities. The most potent compd. to emerge, (23S,24S)-2α-(3-hydroxypropoxy)-24-Pr exhibited almost 1000-fold stronger antagonistic activity (IC50 = 7.4 pM) than I (IC50 = 6.3 nM).
- 217Wiberg, K.; Ljunghall, S.; Binderup, L.; Ljunggren, Ö. Studies on Two New Vitamin D Analogs, EB 1089 and KH 1060: Effects on Bone Resorption and Osteoclast Recruitment in Vitro. Bone 1995, 17 (4), 391– 395, DOI: 10.1016/S8756-3282(95)00246-4[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXpslWktrg%253D&md5=5b9302cde09afb7cb9d5611b917c084aStudies on two new vitamin D analogs, EB 1089 and KH 1060: effects on bone resorption and osteoclast recruitment in vitroWiberg, K.; Ljunghall, S.; Binderup, L.; Ljunggren, Oe.Bone (New York) (1995), 17 (4), 391-5CODEN: BONEDL; ISSN:8756-3282. (Elsevier)The effects on bone resorption of 2 new potent antiproliferative vitamin D3 analogs, EB 1089 and KH 1060, were investigated by studying recruitment of osteoclasts in murine bone marrow cultures and 45Ca release from prelabeled neonatal mouse calvarial bones. Binding studies to vitamin D receptor protein from human osteosarcoma MG-63 cells demonstrated kd values of 8.5 × 10-11 for calcitriol (1α,25(OH)2D3), 6.5 × 10-11 for KH 1060, and 2.7 × 10-10 for EB 1089. 1α,25(OH)2D3 and EB 1089 were equipotent stimulators of osteoclast recruitment in murine bone marrow cultures, with EC50 values of 10-10M, whereas KH 1060 was about 10-fold more potent, with an EC50 of 10-11M. In serum-free media, 1α,25(OH)2D3 enhanced 45Ca release from neonatal mouse calvarial bones with an EC50 of 10-11M, but in the presence of 10% fetal calf serum (FCS) the stimulatory effect was diminished, with a threshold value of 10-10M. EB 1089 stimulated bone resorption with an estd. EC50 of 3 × 10-11M, whereas KH 1060 was about 10-fold more potent than 1α,25(OH)2D3, and it stimulated bone resorption with an EC50 of 10-12M. The effects of EB 1089 and KH 1060 on 45Ca release were not affected by the addn. of 10% FCS. Addn. of vitamin D-binding protein to serum-free incubations of neonatal mouse calvarial bones inhibited the bone-resorbing effect of 1α,25(OH)2D3 but did not affect EB 1089- and KH 1060-induced 45Ca release. These data show that the kd values for the binding to vitamin D receptors are similar to the EC50 values for stimulation of bone resorption and osteoclast differentiation, in vitro, for 1α,25(OH)2D3, EB 1089, and KH 1060. The discrepancy in the effect of FCS on 45Ca release induced by 1α,25(OH)2D3 and the new analogs suggests that EB 1089 and KH 1060 do not bind to vitamin D-binding protein, indicating that pharmacokinetic differences may partially explain their lesser calcemic effects in vivo.
- 218Germain, P.; Chambon, P.; Eichele, G.; Evans, R. M.; Lazar, M. A.; Leid, M.; De Lera, A. R.; Lotan, R.; Mangelsdorf, D. J.; Gronemeyer, H. International Union of Pharmacology. LXIII. Retinoid X Receptors. Pharmacol. Rev. 2006, 58 (4), 760– 772, DOI: 10.1124/pr.58.4.7[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28npsFOhtw%253D%253D&md5=9d9ed3201419f63fab5ca74043cc0a19International Union of Pharmacology. LXIII. Retinoid X receptorsGermain Pierre; Chambon Pierre; Eichele Gregor; Evans Ronald M; Lazar Mitchell A; Leid Mark; De Lera Angel R; Lotan Reuben; Mangelsdorf David J; Gronemeyer HinrichPharmacological reviews (2006), 58 (4), 760-72 ISSN:0031-6997.The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. RARs bind both all-trans- and 9-cis-RA, whereas only the 9-cis-RA stereoisomer binds to RXRs. As RXR/RAR heterodimers, these receptors control the transcription of RA target genes through binding to RA-response elements. This review is focused on the structure, mode of action, ligands, expression, and pharmacology of RXRs. Given their role as common partners to many other members of the nuclear receptor superfamily, these receptors have been the subject of intense scrutiny. Moreover, and despite numerous studies since their initial discovery, RXRs remain enigmatic nuclear receptors, and there is still no consensus regarding their role. Indeed, multiple questions about the actual biological role of RXRs and the existence of an endogenous ligand have still to be answered.
- 219de Lera, A. R.; Bourguet, W.; Altucci, L.; Gronemeyer, H. Design of Selective Nuclear Receptor Modulators: RAR and RXR as a Case Study. Nat. Rev. Drug Discovery 2007, 6 (10), 811– 820, DOI: 10.1038/nrd2398[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFSgsLzN&md5=223ff5473631d321c2e81bb76b986253Design of selective nuclear receptor modulators: RAR and RXR as a case studyde Lera, Angel R.; Bourguet, William; Altucci, Lucia; Gronemeyer, HinrichNature Reviews Drug Discovery (2007), 6 (10), 811-820CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Retinoic acid receptors (RARs) are important drug targets for cancer therapy and prevention, and the potential of rexinoids for the treatment of metabolic diseases is increasingly being recognized. This article reviews recent structural data for RARs and retinoid X receptors (RXRs), discusses strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general. Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are members of the nuclear receptor superfamily whose effects on cell growth and survival can be modulated therapeutically by small-mol. ligands. Although compds. that target these receptors are powerful anticancer drugs, their use is limited by toxicity. An improved understanding of the structural biol. of RXRs and RARs and recent advances in the chem. synthesis of modified retinoid and rexinoid ligands should enable the rational design of more selective agents that might overcome such problems. Here, the authors review structural data for RXRs and RARs, discuss strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general.
- 220Dominguez, M.; Alvarez, S.; de Lera, A. R. Natural and Structure-Based RXR Ligand Scaffolds and Their Functions. Curr. Top. Med. Chem. 2017, 17 (6), 631– 662, DOI: 10.2174/1568026616666160617072521[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1ektbk%253D&md5=1e41e2fd5d7ed6ae48caa38cddbe306dNatural and Structure-based RXR Ligand Scaffolds and Their FunctionsDominguez, Marta; Alvarez, Susana; de Lera, Angel R.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2017), 17 (6), 631-662CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)Retinoid X receptors (RXRs) are promiscuous partners of heterodimeric assocns. with other members of the Nuclear Receptor (NR) superfamily. Through these liaisons RXR ligands ("rexinoids") either transcriptionally activate on their own the "permissive" subclass of heterodimers (PPAR/RXR, LXR/RXR, FXR/RXR) or synergize with partner ligands in the "non-permissive" subclass of heterodimers (RAR/RXR, VDR/RXR and TR/RXR). The nature and extent of the interaction of the ligand-receptor complexes with co-regulators, which is cell and context-dependent, results ultimately in transcriptional modulation of cognate gene networks. RXR modulators hold therapeutical potential for the treatment of cancer and other diseases related to nutrient acquisition and disposal, among them metabolic diseases. A rexinoid (bexarotene) has indeed reached the clinic for the treatment of cutaneous T-cell lymphoma. The modulation of RXR function by rexinoids acting as agonists, partial agonists, inverse agonists or antagonists is encoded in the structure of the ligand-receptor complexes. A very large no. of rexinoids with a wide structural diversity has been published. In addn. to natural products and other ligands discovered by HTS or mere serendipity, most rexinoids have been rationally designed based on the structures of existing complexes with RXR detd. by X-Ray or based on Mol. Modeling. Although the structural rationale for the modulation of the ligand-receptor complexes is reasonably well understood, it has not yet been possible to predict the correlation between ligand structure and physiol. response, particularly in the case of heterodimer-selective rexinoids.
- 221Chaikuad, A.; Pollinger, J.; Rühl, M.; Ni, X.; Kilu, W.; Heering, J.; Merk, D. Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms. Int. J. Mol. Sci. 2020, 21 (22), 8457, DOI: 10.3390/ijms21228457[Crossref], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFyhtLjL&md5=9f8ebbf6fe24cd7a000346b87de48e9bComprehensive set of tertiary complex structures and palmitic acid binding provide molecular insights into ligand design for RXR isoformsChaikuad, Apirat; Pollinger, Julius; Ruehl, Michael; Ni, Xiaomin; Kilu, Whitney; Heering, Jan; Merk, DanielInternational Journal of Molecular Sciences (2020), 21 (22), 8457CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically obsd. for RXR agonists, likely due to the lack of isoform selectivity, limit chemotherapeutic application of currently available RXR ligands. The three human RXR isoforms exhibit different expression patterns; however, they share high sequence similarity, presenting a major obstacle toward the development of subtype-selective ligands. Here, we report the discovery of the satd. fatty acid, palmitic acid, as an RXR ligand and disclose a uniform set of crystal structures of all three RXR isoforms in an active conformation induced by palmitic acid. A structural comparison revealed subtle differences among the RXR subtypes. We also obsd. an ability of palmitic acid as well as myristic acid and stearic acid to induce recruitment of steroid receptor co-activator 1 to the RXR ligand-binding domain with low micromolar potencies. With the high, millimolar endogenous concns. of these highly abundant lipids, our results suggest their potential involvement in RXR signaling.
- 222Schierle, S.; Merk, D. Therapeutic Modulation of Retinoid X Receptors - SAR and Therapeutic Potential of RXR Ligands and Recent Patents. Expert Opin. Ther. Pat. 2019, 29 (8), 605– 621, DOI: 10.1080/13543776.2019.1643322[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVWjsbbK&md5=963ecfd85c230fdfa5846a41beb5dd3cTherapeutic modulation of retinoid X receptors - SAR and therapeutic potential of RXR ligands and recent patentsSchierle, Simone; Merk, DanielExpert Opinion on Therapeutic Patents (2019), 29 (8), 605-621CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)A review. Retinoid X receptor (RXR) agonists have a limited role in cancer therapy with bexarotene and alitretinoin as approved drugs but their use is limited by adverse effects. Several evidence from in vitro, in vivo, and small clin. studies points to various further potential applications of RXR ligands in neurodegenerative and inflammatory diseases. The authors review known RXR ligand classes with their key structure-activity relationships and recent reports on pharmacol. effects of RXR modulation. Based on these aspects, the authors evaluate recent patents claiming novel RXR ligands or their use. While the use of RXR modulators has been claimed in several novel and promising indications, little progress has been made in the development of innovative rexinoids with improved (subtype-)selectivity. Next-generation RXR modulators that selectively target the RXR subtypes for individual indications may be required to exhaustively exploit the therapeutic potential of RXRs.
- 223Egea, P. F.; Mitschler, A.; Moras, D. Molecular Recognition of Agonist Ligands by RXRs. Mol. Endocrinol. 2002, 16 (5), 987– 997, DOI: 10.1210/mend.16.5.0823[Crossref], [PubMed], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjsFGhsL8%253D&md5=c1fa963b975b03e1191d193df8962627Molecular recognition of agonist ligands by RXRsEgea, Pascal F.; Mitschler, Andre; Moras, DinoMolecular Endocrinology (2002), 16 (5), 987-997CODEN: MOENEN; ISSN:0888-8809. (Endocrine Society)The nuclear receptor RXR is an obligate partner in many signal transduction pathways. We report the high-resoln. structures of two complexes of the human RXRα ligand-binding domain specifically bound to two different and chem. unrelated agonist compds.: docosahexaenoic acid, a natural deriv. of eicosanoic acid, present in mammalian cells and recently identified as a potential endogenous RXR ligand in the mouse brain, and the synthetic ligand BMS 649. In both structures the RXR-ligand-binding domain forms homodimers and exhibits the active conformation previously obsd. with 9-cis-RA. Anal. of the differences in ligand-protein contacts (predominantly van der Waals forces) and binding cavity geometries and vols. for the several agonist-bound RXR structures clarifies the structural features important for ligand recognition. The L-shaped ligand-binding pocket adapts to the diverse ligands, esp. at the level of residue N306, which might thus constitute a new target for drug-design. Despite its highest affinity 9-cis-RA displays the lowest no. of ligand-protein contacts. These structural results support the idea that docosahexaenoic acid and related fatty acids could be natural agonists of RXRs and question the real nature of the endogenous ligand(s) in mammalian cells.
- 224Zetterstrom, R. H.; Lindqvist, E.; De Urquiza, A. M.; Tomac, A.; Eriksson, U.; Perlmann, T.; Olson, L. Role of Retinoids in the CNS : Differential Expression of Retinoid Binding Proteins and Receptors and Evidence for Presence of Retinoic Acid. Eur. J. Neurosci. 1999, 11 (2), 407– 416, DOI: 10.1046/j.1460-9568.1999.00444.x[Crossref], [PubMed], [CAS], Google Scholar224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1M7ntF2gsg%253D%253D&md5=cd0fdeef9529344c16ec83832bc07216Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acidZetterstrom R H; Lindqvist E; Mata de Urquiza A; Tomac A; Eriksson U; Perlmann T; Olson LThe European journal of neuroscience (1999), 11 (2), 407-16 ISSN:0953-816X.Retinoic acid (RA), a retinoid metabolite, acts as a gene regulator via ligand-activated transcription factors, known as retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both existing in three different subtypes, alpha, beta and gamma. In the intracellular regulation of retinoids, four binding proteins have been implicated: cellular retinol binding protein (CRBP) types I and II and cellular retinoic acid binding protein (CRABP) types I and II. We have used in situ hybridization to localize mRNA species encoding CRBP- and CRABP I and II as well as all the different nuclear receptors in the developing and adult rat and mouse central nervous system (CNS), an assay to investigate the possible presence of RA, and immunohistochemistry to also analyse CRBP I- and CRABP immunoreactivity (IR). RXRbeta is found in most areas while RARalpha and -beta and RXRalpha and -gamma show much more restricted patterns of expression. RARalpha is found in cortex and hippocampus and RARbeta and RXRgamma are both highly expressed in the dopamine-innervated areas caudate/putamen, nucleus accumbens and olfactory tubercle. RARgamma could not be detected in any part of the CNS. Using an in vitro reporter assay, we found high levels of RA in the developing striatum. The caudate/putamen of the developing brain showed strong CRBP I-IR in a compartmentalized manner, while at the same time containing many evenly distributed CRABP I-IR neurons. The CRBP I- and CRABP I-IR patterns were closely paralleled by the presence of the corresponding transcripts. The specific expression pattern of retinoid-binding proteins and nuclear retinoid receptors as well as the presence of RA in striatum suggests that retinoids are important in many brain structures and emphasizes a role for retinoids in gene regulatory events in postnatal and adult striatum.
- 225Ferré, S.; Fredholm, B. B.; Morelli, M.; Popoli, P.; Fuxe, K. Adenosine – Dopamine Receptor – Receptor Interactions as an Integrative Mechanism in the Basal Ganglia. Trends Neurosci. 1997, 20 (10), 482– 487, DOI: 10.1016/S0166-2236(97)01096-5[Crossref], [PubMed], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmsFKisr4%253D&md5=986e1e4f2207c6844f000db83557cca8Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal gangliaFerre, Sergi; Fredholm, Bertil B.; Morelli, Micaela; Popoli, Patrizia; Fuxe, KjellTrends in Neurosciences (1997), 20 (10), 482-487CODEN: TNSCDR; ISSN:0166-2236. (Elsevier)A review, with 48 refs. Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the motor depressant effects of adenosine receptor agonists and the motor stimulant effects of adenosine receptor antagonists, such as caffeine. The GABAergic striatopallidal neurons are regulated by interacting adenosine A2A and dopamine D2 receptors. The GABAergic striatonigral and striatoentopeduncular neurons seem to be regulated by interacting adenosine A1 and dopamine D1 receptors. Furthermore, behavioral studies have revealed interactions between adenosine A2A and dopamine D1 receptors that occur at the network level. These adenosine-dopamine receptor-receptor interactions might offer new therapeutic leads for basal ganglia disorders.
- 226Moreno, S.; Farioli-Vecchioli, S.; Cerù, M. P. Immunolocalization of Peroxisome Proliferator-Activated Receptors and Retinoid X Receptors in the Adult Rat CNS. Neuroscience 2004, 123 (1), 131– 145, DOI: 10.1016/j.neuroscience.2003.08.064[Crossref], [PubMed], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXps1Ontb0%253D&md5=436ec9624d1520e4270028d128342b92Immunolocalization of peroxisome proliferator-activated receptors and retinoid x receptors in the adult rat CNSMoreno, S.; Farioli-Vecchioli, S.; Ceru, M. P.Neuroscience (Oxford, United Kingdom) (2004), 123 (1), 131-145CODEN: NRSCDN; ISSN:0306-4522. (Elsevier Science Ltd.)Peroxisome proliferator-activated and retinoid X receptors (PPARs and RXRs) are transcription factors belonging to the steroid hormone receptor superfamily. Upon activation by their ligands, PPARs and RXRs bind to their target genes as heterodimers. Ligands of these receptors include lipophilic mols., such as retinoids, fatty acids and eicosanoids, the importance of which in the metab. and functioning of the nervous tissue is well documented. The immunohistochem. distribution of PPARs and RXRs in the CNS of the adult rat was studied by means of a sensitive biotinyl-tyramide method. All PPAR (α, β/δ and γ) and RXR (α, β and γ) isotypes were detected and found to exhibit specific patterns of localization in the different areas of the brain and spinal cord. The presence of the nuclear receptors was obsd. in both neuronal and glial cells. While PPAR β/δ and RXR β showed a widespread distribution, α and γ isotypes exhibited a more restricted pattern of expression. The frontal cortex, basal ganglia, reticular formation, some cranial nerve nuclei, deep cerebellar nuclei, and cerebellar Golgi cells appeared rather rich in all studied receptors. Based on our data, we suggest that in the adult CNS, PPARs and RXRs, besides playing roles common to many other tissues, may have specific functions in regulating the expression of genes involved in neurotransmission, and therefore play roles in complex processes, such as aging, neurodegeneration, learning and memory.
- 227Huang, J. K.; Jarjour, A. A.; Nait Oumesmar, B.; Kerninon, C.; Williams, A.; Krezel, W.; Kagechika, H.; Bauer, J.; Zhao, C.; Baron-Van Evercooren, A.; Chambon, P.; Ffrench-Constant, C.; Franklin, R. J. M. Retinoid X Receptor Gamma Signaling Accelerates CNS Remyelination. Nat. Neurosci. 2011, 14 (1), 45– 53, DOI: 10.1038/nn.2702[Crossref], [PubMed], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFajurjL&md5=376bc307b9d9726eb612b6bc8366e733Retinoid X receptor gamma signaling accelerates CNS remyelinationHuang, Jeffrey K.; Jarjour, Andrew A.; Oumesmar, Brahim Nait; Kerninon, Christophe; Williams, Anna; Krezel, Wojciech; Kagechika, Hiroyuki; Bauer, Julien; Zhao, Chao; Baron-Van Evercooren, Anne; Chambon, Pierre; ffrench-Constant, Charles; Franklin, Robin J. M.Nature Neuroscience (2011), 14 (1), 45-53CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)The mol. basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the sep. stages of spontaneous remyelination that follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-γ is a pos. regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacol. target for regenerative therapy in the CNS.
- 228Hanafy, K. A.; Sloane, J. A. Regulation of Remyelination in Multiple Sclerosis. FEBS Lett. 2011, 585 (23), 3821– 3828, DOI: 10.1016/j.febslet.2011.03.048[Crossref], [PubMed], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFSis73P&md5=1fb2590498171cf217c8f19652602321Regulation of remyelination in multiple sclerosisHanafy, Khalid A.; Sloane, Jacob A.FEBS Letters (2011), 585 (23), 3821-3828CODEN: FEBLAL; ISSN:0014-5793. (Elsevier B.V.)A review. Multiple sclerosis is a common demyelinating disease that worsens over the course of disease, a significant problem in clin. management. Disability in MS is significantly promoted by poor repair and remyelination of lesions. Both oligodendrocyte recruitment and maturation defects are seen as major causes of poor remyelination in MS. The mechanisms behind impaired remyelination in animal models include involvement of the Notch1, wnt, and hyaluronan/TLR2 pathways. RXR/PPAR signaling has also more recently been identified as an important regulator of remyelination. The local inflammatory milieu also appears to play crit. and conflicting roles in promotion and inhibition of remyelination in MS. Understanding the forces regulating remyelination in MS represents an exciting and important initial step towards developing therapeutics targeting chronic disability in MS.
- 229Vaz, B.; de Lera, Á. R. Advances in Drug Design with RXR Modulators. Expert Opin. Drug Discovery 2012, 7 (11), 1003– 1016, DOI: 10.1517/17460441.2012.722992[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFOntbzJ&md5=8937d9930d5574a56c13415a954ae1c5Advances in drug design with RXR modulatorsVaz, Belen; de Lera, Angel R.Expert Opinion on Drug Discovery (2012), 7 (11), 1003-1016CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)A review. Introduction: Retinoid X receptors (subtypes RXRα or NR2B1, RXRβ or NR2B2 and RXRγ or NR2B3, which originate from three distinct genes) are promiscuous partners with heterodimeric assocns. to other members of the Nuclear Receptor (NR) superfamily. Some of the heterodimers are "permissive" and transcriptionally active in the presence of either an RXR ligand ("rexinoid") or a NR partner ligand, whereas others are "non-permissive" and unresponsive to rexinoids alone. In rodent models, rexinoids and partner agonists (mainly PPARγ, LXR, FXR) produce beneficial effects on insulin sensitization, diabetes and obesity, but secondary effects have also been noted, such as a raise in tryglyceride levels, suppression of the thyroid hormone axis and induction of hepatomegaly.Areas covered: The authors review recent advances in rexinoid design, including further optimization of known scaffolds, and the discovery of novel RXR modulators by virtual ligand screening or from bioactive natural products. The understanding of rexinoid functions in permissive and non-permissive heterodimers is firmly based on structural knowledge. By strenghtening or disrupting the interaction surface with coregulators rexinoids exert agonist or (partial) antagonist activities. The activity state of the heterodimer can also be fine-tuned by the cellular context and the nature of coregulators.Expert opinion: The synthetic chem. toolbox has provided a panel of agonists, partial (ant)agonists and/or heterodimer-selective rexinoids starting from existing, naturally occurring or serendipitously discovered scaffolds. These compds. have an unexplored therapeutic potential that might overcome some of the current limitations of rexinoids in therapy, such as hypertriglyceridemia.
- 230Koster, K. P.; Smith, C.; Valencia-Olvera, A. C.; Thatcher, G. R. J.; Tai, L. M.; LaDu, M. J. Rexinoids as Therapeutics for Alzheimer’s Disease: Role of APOE. Curr. Top. Med. Chem. 2017, 17 (6), 708– 720, DOI: 10.2174/1568026616666160617090227[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1ektLo%253D&md5=99e3cc09db5b6e42084ea846eb9d9963Rexinoids as Therapeutics for Alzheimer's Disease: Role of APOEKoster, Kevin P.; Smith, Conor; Valencia-Olvera, Ana C.; Thatcher, Gregory R. J.; Tai, Leon M.; LaDu, Mary JoCurrent Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2017), 17 (6), 708-720CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques, composed of amyloid-beta peptide (Aβ) and neurofibrillary tangles, composed of aberrantly phosphorylated tau. APOE4 is the greatest genetic risk factor for AD, increasing risk up to 12- fold with a double allele compared to APOE3. In contrast, APOE2 reduces AD risk ∼2-fold per allele. Accumulating evidence demonstrates that apolipoprotein E4 (apoE4) plays a multifactorial role in AD pathogenesis, although the exact mechanisms remain unclear. Further data support roles for apoE4 as a toxic gain of function or loss of pos. function in AD, a discrepancy that has significant implications for the future of apoE-directed therapeutics. However, recent evidence repurposing retinoid X receptor (RXR) agonists, or rexinoids, for the treatment of AD demonstrates conflicting, though potentially beneficial effects in familial AD-transgenic (FAD-Tg) mouse models. Of particular note is bexarotene (Targretin), a selective rexinoid previously utilized in cancer treatment emerging as a viable candidate for AD clin. trials. However, the mechanism of action of bexarotene and similar rexinoids remains controversial, particularly in the context of human APOE. In addn., rexinoids demonstrate distinct adverse event profiles in humans that may have greater detrimental effects in an elderly AD population. Therefore, this special issue review discusses the implications for rexinoiddirected therapeutic strategies in AD, the potential mechanistic targets, and future directions for the improvement of rexinoid-based therapies in AD.
- 231Corder, E. H.; Saunders, A. M.; Strittmatter, W. J.; Schmechel, D. E.; Gaskell, P. C.; Small, G. W.; Roses, A. D.; Haines, J. L.; Pericak-Vance, M. A. Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer’s Disease in Late Onset Families. Science 1993, 261 (5123), 921– 923, DOI: 10.1126/science.8346443[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmtVWjur8%253D&md5=69f2add123ded907ea61945b1de5b45fGene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset familiesCorder, E. H.; Saunders, A. M.; Strittmatter, W. J.; Schmechel, D. E.; Gaskell, P. C.; Small, G. W.; Roses, A. D.; Haines, J. L.; Pericak-Vance, M. A.Science (Washington, DC, United States) (1993), 261 (5123), 921-3CODEN: SCIEAS; ISSN:0036-8075.The apolipoprotein E type 4 allele (APOE-ε4) is genetically assocd. with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 yr with increasing no. of APOE-ε4 alleles in 42 families with late onset AD. Thus APOE-ε4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-ε4 was virtually sufficient to cause AD by age 80.
- 232Cosentino, S.; Scarmeas, N.; Helzner, E.; Glymour, M. M.; Brandt, J.; Albert, M.; Blacker, D.; Stern, Y. APOE Epsilon 4 Allele Predicts Faster Cognitive Decline in Mild Alzheimer Disease. Neurology 2008, 70 (19), 1842– 1849, DOI: 10.1212/01.wnl.0000304038.37421.cc[Crossref], [PubMed], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c3psFCntw%253D%253D&md5=2e53832aaf6d7afeb5457bcd9171329bAPOE epsilon 4 allele predicts faster cognitive decline in mild Alzheimer diseaseCosentino S; Scarmeas N; Helzner E; Glymour M M; Brandt J; Albert M; Blacker D; Stern YNeurology (2008), 70 (19 Pt 2), 1842-9 ISSN:.OBJECTIVE: To determine whether APOE epsilon 4 predicts rate of cognitive change in incident and prevalent Alzheimer disease (AD). METHODS: Individuals were recruited from two longitudinal cohort studies-the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based)--and were followed for an average of 4 years. Three samples of participants diagnosed with AD, with diverse demographic characteristics and baseline cognitive functioning, were studied: 1) 199 (48%) of the incident WHICAP cases; 2) 215 (54%) of the prevalent WHICAP cases; and 3) 156 (71%) of the individuals diagnosed with AD in the Predictors Study. Generalized estimating equations were used to test whether rate of cognitive change, measured using a composite cognitive score in WHICAP and the Mini-Mental State Examination in Predictors, varied as a function of epsilon 4 status in each sample. RESULTS: The presence of at least one epsilon 4 allele was associated with faster cognitive decline in the incident population-based AD group (p = 0.01). Parallel results were produced for the two prevalent dementia samples only when adjusting for disease severity or excluding the most impaired participants from the analyses. CONCLUSION: APOE epsilon 4 may influence rate of cognitive decline most significantly in the earliest stages of Alzheimer disease.
- 233Khachaturian, A. S.; Corcoran, C. D.; Mayer, L. S.; Zandi, P. P.; Breitner, J. C. S. Apolipoprotein E Epsilon4 Count Affects Age at Onset of Alzheimer Disease, but Not Lifetime Susceptibility: The Cache County Study. Arch. Gen. Psychiatry 2004, 61 (5), 518– 524, DOI: 10.1001/archpsyc.61.5.518[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXkslektbk%253D&md5=477d98c0284ec737d6b66fa4f02cf6b1Apolipoprotein E ε4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The cache county studyKhachaturian, Ara S.; Corcoran, Christopher D.; Mayer, Lawrence S.; Zandi, Peter P.; Breitner, John C. S.Archives of General Psychiatry (2004), 61 (5), 518-524CODEN: ARGPAQ; ISSN:0003-990X. (American Medical Association)The incidence of Alzheimer disease (AD) increases strongly with age, but little is known about the cumulative incidence of AD over a lifetime of 100 yr, or its relationship to the polymorphic APOE locus that encodes apolipoprotein E. APOE is a strong genetic risk factor for AD. The aim was to est. the occurrence of AD as a function of age and no. of APOE ε4 alleles; and to explore evidence for heterogeneity of AD risk related to APOE genotype and to other sources. Nonparametric and parametric survival analyses of AD incidence in prospective longitudinal study. Setting and Participants: A total of 3308 elderly residents of Cache County, Utah. Main Outcome Measures: Cumulative incidence of AD; in mixt. models assuming susceptible and non-susceptible individuals, the proportion of individuals not susceptible to AD at any age. Results: Models that assumed a proportion of invulnerable individuals provided strongly improved fit to the data. These models estd. the 100-yr lifetime incidence of AD at 72%, implying that 28% of individuals would not develop AD over any reasonable life expectancy. We confirmed the acceleration of AD onset in individuals with 1 or, esp., 2 APOE ε4 alleles, but obsd. no meaningful difference in 100-yr lifetime incidence related to no. of ε4 alleles. Conclusions: The APOE ε4 allele acts as a potent risk factor for AD by accelerating onset. However, the risk of AD appears heterogeneous in ways independent of APOE. Some individuals seem destined to escape AD, even over an extended lifespan. Their relative invulnerability may reflect other genes or environmental factors that can be investigated.
- 234Mandrekar-Colucci, S.; Landreth, G. E. Nuclear Receptors as Therapeutic Targets for Alzheimer’s Disease. Expert Opin. Ther. Targets 2011, 15 (9), 1085– 1097, DOI: 10.1517/14728222.2011.594043[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVWnt7zO&md5=b99a95828b8081ef50deea7fda13419bNuclear receptors as therapeutic targets for Alzheimer's diseaseMandrekar-Colucci, Shweta; Landreth, Gary E.Expert Opinion on Therapeutic Targets (2011), 15 (9), 1085-1097CODEN: EOTTAO; ISSN:1472-8222. (Informa Healthcare)A review. Introduction: Alzheimer's disease (AD) is characterized by the accumulation and extensive deposition of amyloid β (Aβ) in the parenchyma of the brain. This accumulation of amyloid is assocd. with perturbations in synaptic function, impairments in energy metab. and induction of a chronic inflammatory response which acts to promote neuronal loss and cognitive impairment. Areas covered: Currently, there are no drugs that target the underlying mechanisms of AD. Here, we propose a class of nuclear receptors as novel and promising new therapeutic targets for AD. This review summarizes the literature on nuclear receptors and their effects on AD-related pathophysiol. Expert opinion: Nuclear receptors are attractive targets for the treatment of AD due to their ability to facilitate degrdn. of Aβ, affect microglial activation and suppress the inflammatory milieu of the brain. Liver X receptor agonists have proven difficult to move into clin. trials as long-term treatment results in hepatic steatosis. It is our view that PPAR-γ activation remains a promising avenue for the treatment for AD; however, the poor BBB permeability of the currently available agonists and the neg. outcome of the Phase III clin. trials are likely to diminish interest in pursuing this target.
- 235Koldamova, R.; Fitz, N. F.; Lefterov, I. ATP-Binding Cassette Transporter A1: From Metabolism to Neurodegeneration. Neurobiol. Dis. 2014, 72A, 13– 21, DOI: 10.1016/j.nbd.2014.05.007
- 236Oram, J. F.; Vaughan, A. M. ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease. Circ. Res. 2006, 99 (10), 1031– 1043, DOI: 10.1161/01.RES.0000250171.54048.5c[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFKgurrK&md5=cd3ea59aeaea73d433b8ccaf958ad881ATP-Binding Cassette Cholesterol Transporters and Cardiovascular DiseaseOram, John F.; Vaughan, Ashley M.Circulation Research (2006), 99 (10), 1031-1043CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)A review. A hallmark of atherosclerotic cardiovascular disease (CVD) is the accumulation of cholesterol in arterial macrophages. Factors that modulate circulating and tissue cholesterol levels have major impacts on initiation, progression, and regression of CVD. Four members of the ATP-binding cassette (ABC) transporter family play important roles in this modulation. ABCA1 and ABCG1 export excess cellular cholesterol into the HDL pathway and reduce cholesterol accumulation in macrophages. ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. All 4 transporters are induced by the same sterol-sensing nuclear receptor system. ABCA1 expression and activity are also highly regulated posttranscriptionally by diverse processes. ABCA1 mutations can cause a severe HDL-deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. ABCG5 or ABCG8 mutations can cause sitosterolemia, in which patients accumulate cholesterol and plant sterols in the circulation and develop premature CVD. Disrupting Abca1 or Abcg1 in mice promotes accumulation of excess cholesterol in macrophages, and manipulating mouse macrophage ABCA1 expression affects atherogenesis. Overexpressing ABCG5 and ABCG8 in mice attenuates diet-induced atherosclerosis in assocn. with reduced circulating and liver cholesterol. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and inhibit transcription of all 4 transporters. Thus, impaired ABC cholesterol transporters might contribute to the enhanced atherogenesis assocd. with common inflammatory and metabolic disorders. Their beneficial effects on cholesterol homeostasis have made these transporters important new therapeutic targets for preventing and reversing CVD.
- 237Tai, L. M.; Mehra, S.; Shete, V.; Estus, S.; Rebeck, G. W.; Bu, G.; Ladu, M. J. Soluble ApoE/Aβ Complex: Mechanism and Therapeutic Target for APOE4-Induced AD Risk. Mol. Neurodegener. 2014, 9, 2, DOI: 10.1186/1750-1326-9-2[Crossref], [PubMed], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivVWktbw%253D&md5=287cdde0f7c3b6c8a35e579c7b19c215Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD riskTai, Leon M.; Mehra, Shipra; Shete, Varsha; Estus, Steve; Rebeck, G. William; Bu, Guojun; La Du, Mary JoMolecular Neurodegeneration (2014), 9 (), 2/1-2/14, 14 pp.CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)A review. The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer's disease (AD) compared to APOE2 and APOE3. Amyloid-β (Aβ), particularly in a sol. oligomeric form (oAβ), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of sol. oAβ are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oAβ levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with Aβ, namely apoE/Aβ complex, modulate Aβ levels. Specifically, we propose that compared to apoE3, apoE4-contg. lipoproteins are less lipidated, leading to less stable apoE4/Aβ complexes, resulting in reduced apoE4/Aβ levels and increased accumulation, particularly of oAβ. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed.
- 238Yu, C.; Youmans, K. L.; Ladu, M. J. Proposed Mechanism for Lipoprotein Remodelling in the Brain. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2010, 1801 (8), 819– 823, DOI: 10.1016/j.bbalip.2010.05.001[Crossref], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntlagsrk%253D&md5=28ccd42cd28cb04cb5415ad8abb8d49aProposed mechanism for lipoprotein remodelling in the brainYu, Chunjiang; Youmans, Katherine L.; La Du, Mary J.Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2010), 1801 (8), 819-823CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)A review. Lipoprotein remodelling in the periphery has been extensively studied. For example, the processing of nascent apoAI particles to cholesterol-loaded HDL lipoproteins during reverse cholesterol transport involves a series of enzymes, transporters in peripheral tissue, as well as other apolipoproteins and lipoproteins. These extensive modifications and interconversions are well defined. Here, we present the hypothesis that a similar process occurs within the blood brain barrier (BBB) via glia-secreted lipid-poor apoE particles undergoing remodelling to become mature central nervous system (CNS) lipoproteins. We further pose several pressing issues and future directions for the study of lipoproteins in the brain.
- 239Cramer, P. E.; Cirrito, J. R.; Wesson, D. W.; Lee, C. Y. D.; Karlo, J. C.; Zinn, A. E.; Casali, B. T.; Restivo, J. L.; Goebel, W. D.; James, M. J.; Brunden, K. R.; Wilson, D. A.; Landreth, G. E. ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models. Science 2012, 335 (6075), 1503– 1506, DOI: 10.1126/science.1217697[Crossref], [PubMed], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktFWksbY%253D&md5=da3768e6a1506dbf5ecc18ef718caaf5ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in Alzheimer's disease Mouse ModelsCramer, Paige E.; Cirrito, John R.; Wesson, Daniel W.; Lee, C. Y. Daniel; Karlo, J. Colleen; Zinn, Adriana E.; Casali, Brad T.; Restivo, Jessica L.; Goebel, Whitney D.; James, Michael J.; Brunden, Kurt R.; Wilson, Donald A.; Landreth, Gary E.Science (Washington, DC, United States) (2012), 335 (6075), 1503-1506CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Alzheimer's disease (AD) is assocd. with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of sol. Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 h. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiol. Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.
- 240Fitz, N. F.; Cronican, A. A.; Lefterov, I.; Koldamova, R. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924– c, DOI: 10.1126/science.1235809[Crossref], [PubMed], [CAS], Google Scholar240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFSrur8%253D&md5=89ae0ba70eb65eed90a2f6d636cc2169Comment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"Fitz, Nicholas F.; Cronican, Andrea A.; Lefterov, Iliya; Koldamova, RadosvetaScience (Washington, DC, United States) (2013), 340 (6135), 924CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 Feb. 2012) demonstrated in a mouse model for Alzheimer's disease (AD) that treatment of APP/PS1ΔE9 mice with bexarotene decreased Aβ pathol. and ameliorated memory deficits. The authors confirm the reversal of memory deficits in APP/PS1ΔE9 mice expressing human APOE3 or APOE4 to the levels of their nontransgenic controls and the significant decrease of interstitial fluid Aβ, but not the effects on amyloid deposition.
- 241Price, A. R.; Xu, G.; Siemienski, Z. B.; Smithson, L. A.; Borchelt, D. R.; Golde, T. E.; Felsenstein, K. M. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924– d, DOI: 10.1126/science.1234089[Crossref], [PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFSrur0%253D&md5=27a71a8aac1a8631bd12c252a1ba7fcfComment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"Price, Ashleigh R.; Xu, Guilian; Siemienski, Zoe B.; Smithson, Lisa A.; Borchelt, David R.; Golde, Todd E.; Felsenstein, Kevin M.Science (Washington, DC, United States) (2013), 340 (6135), 924CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 Feb. 2012) demonstrates short-term bexarotene treatment clearing preexisting β-amyloid deposits from the brains of APP/PS1ΔE9 mice with low amyloid burden, providing a rationale for repurposing this anticancer agent as an Alzheimer's disease (AD) therapeutic. Using a nearly identical treatment regimen, the authors were unable to detect any evidence of drug efficacy despite demonstration of target engagement.
- 242Tesseur, I.; Lo, A. C.; Roberfroid, A.; Dietvorst, S.; Van Broeck, B.; Borgers, M.; Gijsen, H.; Moechars, D.; Mercken, M.; Kemp, J.; D'Hooge, R.; De Strooper, B. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924-e, DOI: 10.1126/science.1233937
- 243Veeraraghavalu, K.; Zhang, C.; Miller, S.; Hefendehl, J. K.; Rajapaksha, T. W.; Ulrich, J.; Jucker, M.; Holtzman, D. M.; Tanzi, R. E.; Vassar, R.; Sisodia, S. S. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924– f, DOI: 10.1126/science.1235505[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFSrurY%253D&md5=c7014b2effed1f3cd1d7d7f194f3311cComment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"Veeraraghavalu, Karthikeyan; Zhang, Can; Miller, Sean; Hefendehl, Jasmin K.; Rajapaksha, Tharinda W.; Ulrich, Jason; Jucker, Mathias; Holtzman, David M.; Tanzi, Rudolph E.; Vassar, Robert; Sisodia, Sangram S.Science (Washington, DC, United States) (2013), 340 (6135), 924CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 Feb. 2012) reported that bexarotene rapidly reduces β-amyloid (Aβ) levels and plaque burden in two mouse models of Aβ deposition in Alzheimer's disease (AD). The authors now report that, although bexarotene reduces sol. Aβ40 levels in one of the mouse models, the drug has no impact on plaque burden in three strains that exhibit Aβ amyloidosis.
- 244Ghosal, K.; Haag, M.; Verghese, P. B.; West, T.; Veenstra, T.; Braunstein, J. B.; Bateman, R. J.; Holtzman, D. M.; Landreth, G. E. A Randomized Controlled Study to Evaluate the Effect of Bexarotene on Amyloid-β and Apolipoprotein E Metabolism in Healthy Subjects. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2016, 2 (2), 110– 120, DOI: 10.1016/j.trci.2016.06.001
- 245Cummings, J. L.; Zhong, K.; Kinney, J. W.; Heaney, C.; Moll-Tudla, J.; Joshi, A.; Pontecorvo, M.; Devous, M.; Tang, A.; Bena, J. Double-Blind, Placebo-Controlled, Proof-of-Concept Trial of Bexarotene in Moderate Alzheimer’s Disease. Alzheimer’s Res. Ther. 2016, 8 (4), 4, DOI: 10.1186/s13195-016-0173-2[Crossref], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXltlenu7o%253D&md5=810dcf97d13126caad88d099c50e7e48Double-blind, placebo-controlled, proof-of-concept trial of bexarotene in moderate Alzheimer's diseaseCummings, Jeffrey L.; Zhong, Kate; Kinney, Jefferson W.; Heaney, Chelcie; Moll-Tudla, Joanne; Joshi, Abhinay; Pontecorvo, Michael; Devous, Michael; Tang, Anne; Bena, JamesAlzheimer's Research & Therapy (2016), 8 (), 4/1-4/9CODEN: ARTLCD; ISSN:1758-9193. (BioMed Central Ltd.)Background: We assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer's disease (AD) in a proof-of-concept trial. Methods: Twenty patients with AD [Mini Mental State Examn. (MMSE) score 10-20 inclusive] with pos. florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 wk. The amyloid imaging result was the primary outcome. Whole-population analyses and prespecified analyses by genotype [apolipoprotein E ε4 (ApoE4) carriers and ApoE4 noncarriers] were conducted. Secondary outcomes included scores on the Alzheimer's Disease Assessment Scale-Cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living scale, MMSE, Clin. Dementia Rating scale, and Neuropsychiatric Inventory. Serum amyloid-β (Aβ) peptide sequences Aβ1-40 and Aβ1-42 measurements were collected as biomarker outcomes. Results: There was no change in the composite or regional amyloid burden when all patients were included in the anal. ApoE4 noncarriers showed a significant redn. in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was obsd. in ApoE4 carriers. There was a significant assocn. between increased serum Aβ1-42 and redns. in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clin. measure. Conclusions: The primary outcome of this trial was neg. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ1-42 in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies.
- 246Lammi, J.; Perlmann, T.; Aarnisalo, P. Corepressor Interaction Differentiates the Permissive and Non-Permissive Retinoid X Receptor Heterodimers. Arch. Biochem. Biophys. 2008, 472 (2), 105– 114, DOI: 10.1016/j.abb.2008.02.003[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXktVKgtrw%253D&md5=6e274e82f219e2964a5e731083fa0feaCorepressor interaction differentiates the permissive and non-permissive retinoid X receptor heterodimersLammi, Johanna; Perlmann, Thomas; Aarnisalo, PiiaArchives of Biochemistry and Biophysics (2008), 472 (2), 105-114CODEN: ABBIA4; ISSN:0003-9861. (Elsevier)Nurr1 is an orphan nuclear receptor regulating transcription both as a monomer and as a heterodimer with retinoid X receptor (RXR). RXR-Nurr1 heterodimers are permissive RXR heterodimers as they activate transcription in response to RXR ligands. In contrast, heterodimers formed by RXR and retinoic acid receptor (RAR) are non-permissive as they activate transcription only upon RAR ligand binding. We studied the mechanism mediating permissiveness and non-permissiveness by creating receptor chimeras between Nurr1 and RAR. We show that the amino-terminal part of the Nurr1 ligand binding domain conveys permissiveness to RXR-Nurr1 heterodimers. This region is involved in interactions with the corepressors SMRT and NcoR. The corepressors were released from RXR-Nurr1 heterodimers by RXR ligand binding. In contrast, RXR ligand increased the interaction between RXR-RAR heterodimers and the corepressors. The corepressors were released only upon binding of RAR ligand. In conclusion, corepressor interaction differentiates the permissive RXR-Nurr1 heterodimers from the non-permissive RXR-RAR heterodimers.
- 247Schrage, K.; Koopmans, G.; Joosten, E. A. J.; Mey, J. Macrophages and Neurons Are Targets of Retinoic Acid Signaling after Spinal Cord Contusion Injury. Eur. J. Neurosci. 2006, 23 (2), 285– 295, DOI: 10.1111/j.1460-9568.2005.04534.x[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD287gslWksw%253D%253D&md5=6ec8f001cb10032cb3ba307e5118a846Macrophages and neurons are targets of retinoic acid signaling after spinal cord contusion injurySchrage Kirsten; Koopmans Guido; Joosten Elbert A J; Mey JorgThe European journal of neuroscience (2006), 23 (2), 285-95 ISSN:0953-816X.The physiological reactions after spinal cord injury are accompanied by local synthesis of the transcriptional activator retinoic acid (RA). RA exerts its effects by binding to retinoic acid receptors (RAR) which heterodimerize with retinoid X receptors (RXR) and then act as ligand-activated transcription factors. To identify possible cellular targets of RA we investigated protein levels and cellular distribution of retinoid receptors in the rat spinal cord at 4, 7, 14 and 21 days after a contusion injury. In the nonlesioned spinal cord, immunoreactivity for RARalpha, RXRalpha, RXRbeta and RXRgamma was localized in the cytosol of neurons, that of RXRalpha and RXRbeta in astrocytes and that of RARalpha, RXRalpha and RXRgamma in some oligodendrocytes. After contusion injury RARalpha and all RXRs appeared in the cell nuclei of reactive microglia and macrophages. This nuclear staining began at 4 days, was most prominent at 7 and 14 days and had decreased at 21 days after injury. A similar nuclear translocation was also observed for the RARalpha, RXRalpha and RXRbeta staining in neurons situated around the border of the contusion. These observations suggest that RA participates as a signal for the physiological responses of microglia and neurons after CNS injury.
- 248Natrajan, M. S.; de la Fuente, A. G.; Crawford, A. H.; Linehan, E.; Nuñez, V.; Johnson, K. R.; Wu, T.; Fitzgerald, D. C.; Ricote, M.; Bielekova, B.; Franklin, R. J. M. Retinoid X Receptor Activation Reverses Age-Related Deficiencies in Myelin Debris Phagocytosis and Remyelination. Brain 2015, 138 (12), 3581– 3597, DOI: 10.1093/brain/awv289[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28zhs12nsw%253D%253D&md5=11739816fdc564568296b576d38b5eafRetinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelinationNatrajan Muktha S; de la Fuente Alerie G; Crawford Abbe H; Franklin Robin J M; Linehan Eimear; Fitzgerald Denise C; Nunez Vanessa; Ricote Mercedes; Johnson Kory R; Wu Tianxia; Bielekova BibianaBrain : a journal of neurology (2015), 138 (Pt 12), 3581-97 ISSN:.The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.
- 249Baer, A. S.; Syed, Y. A.; Kang, S. U.; Mitteregger, D.; Vig, R.; Ffrench-Constant, C.; Franklin, R. J. M.; Altmann, F.; Lubec, G.; Kotter, M. R. Myelin-Mediated Inhibition of Oligodendrocyte Precursor Differentiation Can Be Overcome by Pharmacological Modulation of Fyn-RhoA and Protein Kinase C Signalling. Brain 2009, 132 (2), 465– 481, DOI: 10.1093/brain/awn334[Crossref], [PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M7jt1KlsA%253D%253D&md5=ef148293bfbc13fedf5bef6ff286154eMyelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signallingBaer Alexandra S; Syed Yasir A; Kang Sung Ung; Mitteregger Dieter; Vig Raluca; Ffrench-Constant Charles; Franklin Robin J M; Altmann Friedrich; Lubec Gert; Kotter Mark RBrain : a journal of neurology (2009), 132 (Pt 2), 465-81 ISSN:.Failure of oligodendrocyte precursor cell (OPC) differentiation contributes significantly to failed myelin sheath regeneration (remyelination) in chronic demyelinating diseases. Although the reasons for this failure are not completely understood, several lines of evidence point to factors present following demyelination that specifically inhibit differentiation of cells capable of generating remyelinating oligodendrocytes. We have previously demonstrated that myelin debris generated by demyelination inhibits remyelination by inhibiting OPC differentiation and that the inhibitory effects are associated with myelin proteins. In the present study, we narrow down the spectrum of potential protein candidates by proteomic analysis of inhibitory protein fractions prepared by CM and HighQ column chromatography followed by BN/SDS/SDS-PAGE gel separation using Nano-HPLC-ESI-Q-TOF mass spectrometry. We show that the inhibitory effects on OPC differentiation mediated by myelin are regulated by Fyn-RhoA-ROCK signalling as well as by modulation of protein kinase C (PKC) signalling. We demonstrate that pharmacological or siRNA-mediated inhibition of RhoA-ROCK-II and/or PKC signalling can induce OPC differentiation in the presence of myelin. Our results, which provide a mechanistic link between myelin, a mediator of OPC differentiation inhibition associated with demyelinating pathologies and specific signalling pathways amenable to pharmacological manipulation, are therefore of significant potential value for future strategies aimed at enhancing CNS remyelination.
- 250Kotter, M. R.; Zhao, C.; van Rooijen, N.; Franklin, R. J.M. Macrophage-Depletion Induced Impairment of Experimental CNS Remyelination Is Associated with a Reduced Oligodendrocyte Progenitor Cell Response and Altered Growth Factor Expression. Neurobiol. Dis. 2005, 18 (1), 166– 175, DOI: 10.1016/j.nbd.2004.09.019[Crossref], [PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkslOgtQ%253D%253D&md5=c4c544e09699e93b7c8082e2d9485aeeMacrophage depletion-induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expressionKotter, Mark R.; Zhao, Chao; van Rooijen, Nico; Franklin, Robin J. M.Neurobiology of Disease (2005), 18 (1), 166-175CODEN: NUDIEM; ISSN:0969-9961. (Elsevier)Although macrophages are mediators of CNS demyelination, they are also implicated in remyelination. To examine the role of macrophages in CNS remyelination, adult rats were depleted of monocytes using clodronate liposomes and demyelination induced in the spinal cord white matter using lysolecithin. In situ hybridization for scavenger receptor-B and myelin basic protein (MBP) revealed a transiently impaired macrophage response assocd. with delayed remyelination in liposome-treated animals. Macrophage redn. corresponded with delayed recruitment of PDGFRα+ oligodendrocyte progenitor cells (OPCs), which preceded changes in myelin phagocytosis, indicating a macrophage effect on OPCs independent of myelin debris clearance. Macrophage depletion-induced changes in the mRNA expression of insulin-like growth factor-1 and transforming growth factor β1, but not platelet-derived growth factor-A and fibroblast growth factor-2. Thus, the macrophage response to toxin-induced demyelination influences the growth factor environment, thereby affecting the behavior of OPCs and hence the efficiency of remyelination.
- 251Xu, J.; Drew, P. D. 9-Cis-Retinoic Acid Suppresses Inflammatory Responses of Microglia and Astrocytes. J. Neuroimmunol. 2006, 171 (1–2), 135– 144, DOI: 10.1016/j.jneuroim.2005.10.004[Crossref], [PubMed], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xkt1yi&md5=2661968b0cfe380b2a3cbf4c65352a0a9-Cis-retinoic acid suppresses inflammatory responses of microglia and astrocytesXu, Jihong; Drew, Paul D.Journal of Neuroimmunology (2006), 171 (1-2), 135-144CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)Retinoic acid (RA) regulates a wide range of biol. process, including inflammation. Previously, RA was shown to inhibit the clin. signs of exptl. autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The current study investigated the effects of 9-cis-RA on primary mouse microglia and astrocytes, two cell types implicated in the pathol. of MS and EAE. The studies demonstrated that 9-cis-RA inhibited the prodn. of nitric oxide (NO) as well as the pro-inflammatory cytokines TNF-α, IL-1β and IL-12 p40 by LPS-stimulated microglia. However, this retinoid had no effect on IL-6 secretion and increased MCP-1 prodn. by LPS-stimulated microglia. In LPS-stimulated astrocytes, 9-cis-RA inhibited NO and TNF-α prodn. but had not effect on IL-1β, IL-6 and MCP-1 secretion. These results suggest that RA modulates EAE, at least in part, by suppressing the prodn. of NO and specific inflammatory cytokines from activated glia and suggests that RA might be effective in the treatment of MS.
- 252Chandraratna, R. A.; Sanders, M. E. WO2017/075607 Treatment of Nervous System Disorders Using Combinations of RXR Agonists and Thyroid Hormones, IO Ther. INC, 2017.
- 253Volle, D. H. Nuclear Receptors as Pharmacological Targets, Where Are We Now?. Cell. Mol. Life Sci. 2016, 73 (10), 3777– 3780, DOI: 10.1007/s00018-016-2327-6[Crossref], [PubMed], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhtlalt77P&md5=f797c4ae6c54eb144c95ce13dbb6ca48Nuclear receptors as pharmacological targets, where are we now?Volle, David H.Cellular and Molecular Life Sciences (2016), 73 (20), 3777-3780CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Basel)Knowledge of integrative physiol. is a major challenge for scientists, as even small deregulation could lead to diseases. Cells communicate with each other to control many processes such as growth, migration, survival, or differentiation. Such interaction could be achieved via several mechanisms either through cell-cell interactions and/or through the signaling of mols. that bind to receptors on the membrane or in the target cells. The produced mols. could have either autocrine, paracrine stimulations, or even act on distant organs (endocrine signaling).
- 254Levin, A. A.; Sturzenbecker, L. J.; Kazmer, S.; Bosakowski, T.; Huselton, C.; Allenby, G.; Speck, J.; Kratzeisen, C.; Rosenberger, M.; Lovey, A.; Grippo, J. F. 9-Cis Retinoic Acid Stereoisomer Binds and Activates the Nuclear Receptor RXR Alpha. Nature 1992, 355 (6358), 359– 361, DOI: 10.1038/355359a0[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XhtVSisL0%253D&md5=b9e901de55bf245c7459cfde7cc6b63a9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRαLevin, Arthur A.; Sturzenbecker, Laurie J.; Kazmer, Sonja; Bosakowski, Thomas; Huselton, Christine; Allenby, Gary; Speck, Jeffrey; Kratzeisen, C.; Rosenberger, Michael; et al.Nature (London, United Kingdom) (1992), 355 (6358), 359-61CODEN: NATUAS; ISSN:0028-0836.The activity of retinoids is thought to be mediated by interactions with 2 subfamilies of nuclear retinoic acid receptors, RAR and RXR. The RARs bind all-trans retinoic acid (t-RA) with high affinity and alter gene expression as a consequence of this direct ligand interaction. RXRα is activated by t-RA, yet has little binding affinity for this ligand. t-RA may be converted to a more proximate ligand that directly binds and activates RXRα, and a method of nuclear receptor-dependent ligand trapping was developed to test this hypothesis. A stereoisomer of retinoic acid, 9-cis retinoic acid, which directly binds and activates RXRα was identified. These results suggest a new role for isomerization in the physiol. of natural retinoids.
- 255Goldstein, J. T.; Dobrzyn, A.; Clagett-Dame, M.; Pike, J. W.; Deluca, H. F. Isolation and Characterization of Unsaturated Fatty Acids as Natural Ligands for the Retinoid-X Receptor. Arch. Biochem. Biophys. 2003, 420 (1), 185– 193, DOI: 10.1016/j.abb.2003.09.034[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXovVWgtb8%253D&md5=d64099a06d2497c3d9769ce26cdb53acIsolation and characterization of unsaturated fatty acids as natural ligands for the retinoid-X receptorGoldstein, Jonathan T.; Dobrzyn, Agnieszka; Clagett-Dame, Margaret; Pike, J. Wesley; DeLuca, Hector F.Archives of Biochemistry and Biophysics (2003), 420 (1), 185-193CODEN: ABBIA4; ISSN:0003-9861. (Elsevier Science)The retinoid-X receptor (RXR) is a ligand activated nuclear receptor that is the heterodimer partner for many class II nuclear receptors. Previously identified natural ligands for this receptor include 9-cis retinoic acid (9cRA), docosahexaenoic acid, and phytanic acid. Our studies were performed to det. if there are any unidentified, physiol. important RXR ligands. Agonists for RXR were purified from rat heart and testes lipid exts. with the use of a cell-based reporter assay to monitor RXR activation. Purified active fractions contained a variety of unsatd. fatty acids and components were quantified by gas-liq. chromatog. of derivatized samples. The corresponding fatty acid stds. elicited a similar response in the reporter cell assay. Competition binding anal. revealed that the active fatty acids compete with [3H]9cRA for binding to RXR. Non-esterified fatty acids were analyzed from lipid exts. of isolated heart and testes nuclei and endogenous concns. were found to be within the range of their detd. binding affinities. Our studies reveal tissue dependent profiles of RXR agonists and support the idea of unsatd. fatty acids as physiol. ligands of RXR.
- 256Fitzgerald, P.; Teng, M.; Chandraratna, R. A. S.; Heyman, A.; Allegretto, A. Retinoic Acid Receptor α Expression Correlates with Retinoid-Induced Growth Inhibition of Human Breast Cancer Cells Regardless of Estrogen Receptor Status. Cancer Res. 1997, 57 (13), 2642– 2650[PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2szkvFSltQ%253D%253D&md5=b890df47f31d129e5ae7a395c5b5801eRetinoic acid receptor alpha expression correlates with retinoid-induced growth inhibition of human breast cancer cells regardless of estrogen receptor statusFitzgerald P; Teng M; Chandraratna R A; Heyman R A; Allegretto E ACancer research (1997), 57 (13), 2642-50 ISSN:0008-5472.Retinoic acid receptor (RAR) alpha has been shown to play a role in retinoid-induced growth inhibition of human breast cancer cell lines that express the estrogen receptor (ER). The dogma in the field has been that ER-positive breast cancer cell lines respond to retinoid treatment because they express RAR alpha, whereas ER-negative breast cancer cell lines are refractory to retinoid treatment and have been thought to express little or no RAR alpha. We set out to test several ER-negative breast cancer cell lines for expression of RAR alpha protein and responsiveness to retinoids in growth inhibition assays. Of six ER-negative breast cancer cell lines that were tested, one (SK-BR-3) had high levels of RAR alpha protein as measured by ligand-binding immunoprecipitation (approximately 55 fmol/mg protein) and also displayed sensitivity to growth inhibition by retinoids (9-cis-retinoic acid; EC50, approximately 3 nM). These cells were more sensitive than an ER-positive cell line, T-47D, which expressed approximately 35 fmol RAR alpha/mg total protein (9-cis retinoic acid; EC50, approximately 50-100 nM). Another ER-negative cell line, Hs578T, also expressed RAR alpha (approximately 23 fmol/mg) and was sensitive to retinoid-induced growth inhibition, albeit to a lesser extent than SK-BR-3 or T-47D cells. In contrast, the other ER-negative cell lines tested expressed low (<10 fmol/mg) or no detectable levels of RAR alpha protein and also did not respond to retinoids in growth inhibition assays. A RAR alpha agonist displayed 100 times greater potency than a RARgamma agonist in growth inhibition of both T-47D and SK-BR-3 cells, suggesting RAR alpha involvement in the process. Furthermore, a RAR alpha antagonist completely abolished the growth inhibition induced by RAR agonists, implying that the activity of the agonists is exerted solely through RAR alpha, not RARgamma, which is also expressed in both cell lines. Additionally, although retinoid X receptor (RXR) compounds are weakly active in growth inhibition of the RAR alpha-positive cell lines, they markedly increased the growth-inhibitory activity of RAR ligands. RXR compounds also potentiated the action of the antiestrogen 4-hydroxytamoxifen to inhibit the growth of T-47D cells. These findings have clinical ramifications in that patients with ER-negative tumors that are RAR alpha positive may be candidates for retinoid therapy. Additionally, combinations of RXR ligands with RAR ligands (especially RAR alpha agonists) and/or antiestrogens may have utility in the treatment of breast cancer.
- 257Vuligonda, V.; Thacher, S. M.; Chandraratna, R. A. Enantioselective Syntheses of Potent Retinoid X Receptor Ligands: Differential Biological Activities of Individual Antipodes. J. Med. Chem. 2001, 44 (14), 2298– 2303, DOI: 10.1021/jm0100584[ACS Full Text], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXktFamt7Y%253D&md5=3447f09b74c8ed27806b868dfd0422a2Enantioselective Syntheses of Potent Retinoid X Receptor Ligands: Differential Biological Activities of Individual AntipodesVuligonda, Vidyasagar; Thacher, Scott M.; Chandraratna, Roshantha A. S.Journal of Medicinal Chemistry (2001), 44 (14), 2298-2303CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis and characterization of chiral retinoid X receptor (RXR) selective ligands are described. The enantiomeric acids I and II were synthesized employing an enantioselective cyclopropanation procedure as the key step. Compd. I, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any retinoic acid receptor (RAR) activity. The R,R enantiomer II is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of I was further confirmed in a hyperglycemic animal model (db/db mice). Compd. I lowered glucose by 50% by day 7 at 2 mg/kg, whereas II had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
- 258Boehm, M. F.; McClurg, M. R.; Pathirana, C.; Mangelsdorf, D.; White, S. K.; Hebert, J.; Winn, D.; Goldman, M. E.; Heyman, R. A. Synthesis of High Specific Activity [3H]-9-Cis-Retinoic Acid and Its Application for Identifying Retinoids with Unusual Binding Properties. J. Med. Chem. 1994, 37 (3), 408– 414, DOI: 10.1021/jm00029a013[ACS Full Text], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXjt1eru7g%253D&md5=5fc66f91aa7f4a7f49c42588b1087272Synthesis of high specific activity tritium-labeled [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding propertiesBoehm, Marcus F.; McClurg, Michael R.; Pathirana, Charles; Mangelsdorf, David; White, Steven K.; Hebert, Jonathan; Winn, David; Goldman, Mark E.; Heyman, Richard A.Journal of Medicinal Chemistry (1994), 37 (3), 408-14CODEN: JMCMAR; ISSN:0022-2623.All-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an addnl. endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biol. role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, the authors report the synthesis of high specific activity [3H]-9-cis-RA (I) and its application to study the ligand-binding properties of the various retinoid receptor subtypes. The authors examd. the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
- 259Blair, H. A.; Scott, L. J. Alitretinoin : A Review in Severe Chronic Hand Eczema. Drugs 2016, 76 (13), 1271– 1279, DOI: 10.1007/s40265-016-0621-0[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s3is1emsA%253D%253D&md5=7b91f59707edd401724e10f40c753947Alitretinoin: A Review in Severe Chronic Hand EczemaBlair Hannah A; Scott Lesley JDrugs (2016), 76 (13), 1271-1279 ISSN:.Chronic hand eczema is a common but frequently disabling skin condition which poses a significant social and economic burden. Although skin protection measures and topical therapies are fundamental in its management, some patients are refractory to first-line therapy with topical corticosteroids and require systemic treatment. Alitretinoin (9-cis-retinoic acid; Toctino(®)) is an endogenous vitamin A derivative with high binding affinity for both retinoic acid receptors and retinoid X receptors. Alitretinoin is the first systemic treatment to be approved in the EU for use in patients with severe chronic hand eczema unresponsive to potent topical corticosteroids. This article updates an earlier review of alitretinoin in this indication, focusing on recently published data. In clinical trials, treatment with alitretinoin 10 or 30 mg once daily for up to 24 weeks improved the severity and extent of severe chronic hand eczema in adults, with significantly more alitretinoin than placebo recipients achieving ratings of 'clear' or 'almost clear' hands on the Physician Global Impression of Change scale. For the most part, data obtained in real-world studies were consistent with those observed in clinical trials. Alitretinoin was generally well tolerated, with most adverse events being reversible, dose-dependent and of mild or moderate severity. Thus, oral alitretinoin is a useful treatment option for patients with severe chronic hand eczema unresponsive to potent topical corticosteroids.
- 260Cheer, S. M.; Foster, R. H. Alitretinoin. Am. J. Clin. Dermatol. 2000, 1 (5), 307– 314, DOI: 10.2165/00128071-200001050-00005[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MnltVCitw%253D%253D&md5=830a8d9c36f42f0638a5c43ccc10c40fAlitretinoinCheer S M; Foster R HAmerican journal of clinical dermatology (2000), 1 (5), 307-14; discussion 315-6 ISSN:1175-0561.Alitretinoin is a retinoid receptor pan-agonist, which has been investigated in the treatment of Kaposi's sarcoma (KS). Binding with high affinity to all known retinoid receptors, alitretinoin is thought to regulate proliferation, differentiation, and apoptosis of KS cells. Significantly more patients experienced complete or partial responses [according to the AIDS Clinical Trials Group (ACTG) criteria for topical treatment of cutaneous KS] with alitretinoin 0.1% gel 2 to 4 times daily than with vehicle gel in 2 phase III, multicenter, 12-week, randomized, double-blind clinical trials of patients with AIDS-related KS (35 vs 18%, p = 0.002 and 37 vs 7%, p = 0.00003, respectively). Responses were also observed in patients refractory to prior systemic or topical anti-KS therapies. In an intent-to-treat analysis in a phase II trial, 37% of patients with AIDS-related KS receiving alitretinoin capsules 60 to 100 mg/m2/day demonstrated either complete or partial responses (determined by ACTG criteria). The majority of adverse events associated with alitretinoin 0.1% gel were classified as either mild or moderate, occurred at the site of application and were reversible. In both phase III trials, rash was the most common adverse event. The most common adverse events in patients taking alitretinoin capsules included headache, dry skin, rash, alopecia, exfoliative dermatitis, and hyperlipidemia.
- 261Son, J. H.; Park, S. Y.; Cho, Y. S.; Byun, Y. S.; Chung, B. Y.; Cho, H. J.; Kim, H. O.; Park, C. W. Two Cases of Successful Treatment of Refractory Chronic Inflammatory Skin Disease, Atopic Dermatitis and Psoriasis with Oral Alitretinoin. Ann. Dermatol. 2017, 29 (4), 503– 506, DOI: 10.5021/ad.2017.29.4.503[Crossref], [PubMed], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cfivFSiug%253D%253D&md5=9c6599e56467da05879d28475a5fe8b0Two Cases of Successful Treatment of Refractory Chronic Inflammatory Skin Disease, Atopic Dermatitis and Psoriasis with Oral AlitretinoinSon Jee Hee; Park Sook Young; Cho Yong Se; Byun Yun Sun; Chung Bo Young; Kim Hye One; Park Chun Wook; Cho Hee JinAnnals of dermatology (2017), 29 (4), 503-506 ISSN:1013-9087.There is no expanded citation for this reference.
- 262Rühl, R.; Krzyzosiak, A.; Niewiadomska-Cimicka, A.; Rochel, N.; Szeles, L.; Vaz, B.; Wietrzych-Schindler, M.; Álvarez, S.; Szklenar, M.; Nagy, L.; de Lera, A. R.; Krezel, W. 9-Cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice. PLoS Genet. 2015, 11 (6), e1005213, DOI: 10.1371/journal.pgen.1005213
- 263de Lera, Á.; Krezel, W.; Rühl, R. An Endogenous Mammalian Retinoid X Receptor Ligand, at Last!. ChemMedChem 2016, 11 (10), 1027– 1037, DOI: 10.1002/cmdc.201600105[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntlSrtbo%253D&md5=d3f6d42cfedcd86ff2b8ac57062a51f4An Endogenous Mammalian Retinoid X Receptor Ligand, At Last!de Lera, Angel R.; Krezel, Wojciech; Ruehl, RalphChemMedChem (2016), 11 (10), 1027-1037CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)9-Cis-Retinoic acid was identified and claimed to be the endogenous ligand of the retinoid X receptors (RXRs) in 1992. Since then, the endogenous presence of this compd. has never been rigorously confirmed. Instead, concerns have been raised by other groups that have reported that 9-cis-retinoic acid is undetectable or that its presence occurs at very low levels. Furthermore, these low levels could not satisfactorily explain the physiol. activation of RXR. Alternative ligands, among them various lipids, have also been identified, but also did not fulfill criteria for rigorous endogenous relevance, and their consideration as bona fide endogenous mammalian RXR ligand has likewise been questioned. Recently, novel studies claim that the satd. analog 9-cis-13,14-dihydroretinoic acid functions as an endogenous physiol. relevant mammalian RXR ligand.
- 264Neuringer, M.; Anderson, G. J.; Connor, W. E. The Essentiality of N-3 Fatty Acids for the Development and Function of the Retina and Brain. Annu. Rev. Nutr. 1988, 8, 517– 541, DOI: 10.1146/annurev.nu.08.070188.002505[Crossref], [PubMed], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXlsVyhur8%253D&md5=b1a666895515541a6a60cff4933528ceThe essentiality of n-3 fatty acids for the development and function of the retina and brainNeuringer, Martha; Anderson, Gregory J.; Connor, William E.Annual Review of Nutrition (1988), 8 (), 517-41CODEN: ARNTD8; ISSN:0199-9885.A review, with 170 refs., on the tissue distribution of n-3 fatty acids, their accumulation during development, their dietary deficiency, and their functional effects in biol. membranes.
- 265Bourguet, W.; Vivat, V.; Wurtz, J.-M.; Chambon, P.; Gronemeyer, H.; Moras, D. Crystal Structure of a Heterodimeric Complex of RAR and RXR Ligand-Binding Domains. Mol. Cell 2000, 5 (2), 289– 298, DOI: 10.1016/S1097-2765(00)80424-4[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhslyhtLw%253D&md5=5cb4369df1bd81d12151749e128c626bCrystal structure of a heterodimeric complex of RAR and RXR ligand-binding domainsBourguet, William; Vivat, Valerie; Wurtz, Jean-Marie; Chambon, Pierre; Gronemeyer, Hinrich; Moras, DinoMolecular Cell (2000), 5 (2), 289-298CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)The crystal structure of a heterodimer between the ligand-binding domains (LBDs) of the human RARα bound to a selective antagonist and the constitutively active mouse RXRαF318A mutant shows that, pushed by a bulky extension of the ligand, RARα helix H12 adopts an antagonist position. The unexpected presence of a fatty acid in the ligand-binding pocket of RXRαF318A is likely to account for its apparent "constitutivity.". Specific conformational changes suggest the structural basis of pure and partial antagonism. The RAR-RXR heterodimer interface is similar to that obsd. in most nuclear receptor (NR) homodimers. A correlative anal. of 3D structures and sequences provides a novel view on dimerization among members of the nuclear receptor superfamily.
- 266Heald, P.; Mehlmauer, M.; Martin, A. G.; Crowley, C. A.; Yocum, R. C.; Reich, S. D. Topical Bexarotene Therapy for Patients with Refractory or Persistent Early-Stage Cutaneous T-Cell Lymphoma: Results of the Phase III Clinical Trial. J. Am. Acad. Dermatol. 2003, 49 (5), 801– 815, DOI: 10.1016/S0190-9622(03)01475-0[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3svpvV2rsw%253D%253D&md5=0bf3c93a5ca34df3c0eb5f01c908c19cTopical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trialHeald Peter; Mehlmauer Marilyn; Martin Ann G; Crowley Constance A; Yocum Richard C; Reich Steven DJournal of the American Academy of Dermatology (2003), 49 (5), 801-15 ISSN:0190-9622.OBJECTIVES: We sought to determine the safety and efficacy of topical bexarotene (Targretin; Ligand Pharmaceuticals, La Jolla, Calif) gel 1% in patients with refractory or persistent early-stage cutaneous T-cell lymphoma. METHODS: We conducted a multinational, open-label, phase III study of 50 patients with stage IA to IIA cutaneous T-cell lymphoma. The primary end point classification was the overall complete and partial response rate by the higher of 2 measures: the Physician's Global Assessment of Clinical Condition or the Composite Assessment of Index Lesion Disease Severity. RESULTS: The overall response rates for the Physician's Global Assessment of Clinical Condition, Composite Assessment of Index Lesion Disease Severity, and primary end point classification were 44%, 46%, and 54%, respectively. The most common adverse events possibly related to study medication were mild to moderate irritant dermatitis, pruritus, pain (ie, primarily burning at application site), and skin disorder (eg, skin inflammation, excoriation, and new lesions). There were no serious treatment-related adverse events. CONCLUSIONS: Topical bexarotene gel was generally well tolerated and demonstrated substantial efficacy in patients with refractory or persistent early-stage cutaneous T-cell lymphoma.
- 267Wong, S. F. Oral Bexarotene in the Treatment of Cutaneous T-Cell Lymphoma. Ann. Pharmacother. 2001, 35 (9), 1056– 1065, DOI: 10.1345/aph.10223[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXntlajtL8%253D&md5=8b2a41ac4a91eb75bef26c0f752dcaa2Oral bexarotene in the treatment of cutaneous T-cell lymphomaWong, Siu-FunAnnals of Pharmacotherapy (2001), 35 (9), 1056-1065CODEN: APHRER; ISSN:1060-0280. (Harvey Whitney Books Co.)A review. Objective: To review the preclin. and clin. information related to oral bexarotene approved by the Food and Drug Administration for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy. Data Sources: Literature accessed through MEDLINE (from 1990 to July 2000) and provided by the manufacturer. Key search terms included bexarotene, Targretin, LGD1069, and cutaneous T-cell lymphoma. Data Synthesis: The management of CTCL remains controversial due to its rarity in the US and its heterogeneity. An evaluation focusing on the pharmacol. of bexarotene and its role in the management of the different stages of CTCL was conducted. Conclusions: Bexarotene has demonstrated activity in the treatment of CTCL. The oral route of administration and the adverse effect profile of bexarotene appear to make this drug a favorable option for the treatment of CTCL compared with other systemic therapies. Phase III randomized studies are needed to det. the clin. benefits of bexarotene as monotherapy or combination therapy in the treatment of CTCL.
- 268Boehm, M. F.; Zhang, L.; Badea, B. A.; White, S. K.; Mais, D. E.; Berger, E.; Suto, C. M.; Goldman, M. E.; Heyman, R. A. Synthesis and Structure-Activity Relationships of Novel Retinoid X Receptor-Selective Retinoids. J. Med. Chem. 1994, 37 (18), 2930– 2941, DOI: 10.1021/jm00044a014[ACS Full Text], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmsFKjt7g%253D&md5=90003c75aa4fd4934ad3aeb0773119f2Synthesis and Structure-Activity Relationships of Novel Retinoid X Receptor-Selective RetinoidsBoehm, Marcus F.; Zhang, Lin; Badea, Beth Ann; White, Steven K.; Mais, Dale E.; Berger, Elaine; Suto, Carla M.; Goldman, Mark E.; Heyman, Richard A.Journal of Medicinal Chemistry (1994), 37 (18), 2930-41CODEN: JMCMAR; ISSN:0022-2623.Two series of potent retinoid X receptor (RXR)-selective compds. were designed and synthesized based upon recent observation that(E)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl]benzoic acid binds and transactivates only the retinoic acid receptor (RAR) subtypes whereas its 3-Me deriv. binds and transactivates both the RAR and RXR subfamilies. Functional groups in the 3-position of the tetrahydronaphthalenes I [R = H, alkyl, halo, OH, OMe; X = O, CH2] results in compds. which elicit potent and selective activation of the RXR class. Such RXR-selective compds. offer pharmacol. tools for elucidating the biol. role of the individual retinoid receptors with which they interact. Activation profiles in cotransfection and competitive binding assays as well as mol. modeling calcns. demonstrate crit. structural determinants that confer selectivity for members of the RXR subfamily. The most potent compd. of these series, I [R = Me, X = CH2], is the first RXR-selective retinoid (designated as LGD1069) to enter clin. trials for cancer indications.
- 269Howell, S. R.; Shirley, M. A.; Grese, T. A.; Neel, D. A.; Wells, K. E.; Ulm, E. H. Bexarotene Metabolism in Rat, Dog, and Human, Synthesis of Oxidative Metabolites, and in Vitro Activity at Retinoid Receptors. Drug Metab. Dispos. 2001, 29 (7), 990– 998[PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXksFCntrg%253D&md5=b25bdaa09d196f1c09f2db869b0b2be2Bexarotene metabolism in rat, dog, and human, synthesis of oxidative metabolites, and in vitro activity at retinoid receptorsHowell, Stanley R.; Shirley, Michael A.; Grese, Timothy A.; Neel, David A.; Wells, Kirk E.; Ulm, Edgar H.Drug Metabolism and Disposition (2001), 29 (7), 990-998CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)The metab. of bexarotene, a rexinoid recently approved in the United States for treatment of cutaneous T-cell lymphoma, was studied using liver slices from untreated rats and dogs, liver microsomes from untreated and pretreated rats, and pooled human liver microsomes. Metabolite profiles were examd. in bile and plasma from rats and dogs, and plasma from humans treated with bexarotene. Four metabolites, racemic 6-hydroxy-bexarotene, racemic 7-hydroxy-bexarotene, 6-oxo-bexarotene, and 7-oxo-bexarotene, were synthesized and their binding to, and transactivation of retinoid receptors were examd. Qual. similar metabolite profiles were obsd. in the microsomal and liver slice exts.; the predominant metabolites were 6-hydroxy-bexarotene and glucuronides of parent or hydroxylated metabolites. Pretreatment of rats with bexarotene induced hepatic microsomal bexarotene metab. The hydroxy and oxo metabolites were obsd. in plasma of rats, dogs, and humans treated with bexarotene and 6-hydroxy-bexarotene was a major circulating metabolite. The oxidative metabolites were more abundant relative to parent in plasma from humans than from rat or dog. The predominant biliary metabolites in rat and dog were bexarotene acyl glucuronide and a glucuronide of oxidized bexarotene, resp. Since bexarotene elimination is primarily biliary in these species, these metabolites represent the main bexarotene metabolites in rats and dogs. The binding of synthetic metabolites to retinoid receptors was much reduced relative to parent compd. The metabolites exhibited minimal activity in transactivating retinoic acid receptors and had reduced activity at retinoid X receptors relative to bexarotene. Thus, while there is substantial systemic exposure to the oxidative metabolites of bexarotene, they are unlikely to elicit significant retinoid receptor activation following bexarotene administration.
- 270Wang, Y.; Rong, J.; Zhang, J.; Liu, Y.; Meng, X.; Guo, H.; Liu, H.; Chen, L. Morphology, in Vivo Distribution and Antitumor Activity of Bexarotene Nanocrystals in Lung Cancer. Drug Dev. Ind. Pharm. 2017, 43 (1), 132– 141, DOI: 10.1080/03639045.2016.1225752[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVGjs7zO&md5=cf1605f1fa77229dc3fc9046d51fa36dMorphology, in vivo distribution and antitumor activity of bexarotene nanocrystals in lung cancerWang, Yongjie; Rong, Jinghong; Zhang, Jiaozhen; Liu, Yu; Meng, Xuelian; Guo, Hejian; Liu, Hongsheng; Chen, LijiangDrug Development and Industrial Pharmacy (2017), 43 (1), 132-141CODEN: DDIPD8; ISSN:0363-9045. (Taylor & Francis Ltd.)The objective of this study was to develop and evaluate the morphol., biodistribution and antitumor activity of bexarotene nanocrystals delivery system. The morphol. was investigated using SEM (SEM), transmission electron microscopy (TEM), at. force microscope and bexarotene nanocrystals exhibited the advantages of making the efficacy more steady and durable compared with control group in lung with less cardiac accumulation as shown by biodistribution studies in vivo. In addn., MTT assay, flow cytometry anal., observation of morphol. changes and apoptotic body demonstrated that bexarotene nanocrystals could significantly enhance the in vitro cytotoxicity and induced G1 cycle arrest and apoptosis against A549 cells. Also, bexarotene nanocrystals had significant antitumor activity in mice bearing A549 cell line. This finding was correlated with both in vitro and in vivo. Thereby, the overall results suggest that the bexarotene nanocrystals represent a potential source of medicine, which made bexarotene nanocrystals a promising candidate for the treatment of lung cancer.
- 271Lowenthal, J.; Hull, S. C.; Pearson, S. D. The Ethics of Early Evidence - Preparing for a Possible Breakthrough in Alzheimer’s Disease. N. Engl. J. Med. 2012, 367 (6), 488– 490, DOI: 10.1056/NEJMp1203104[Crossref], [PubMed], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1SisrbO&md5=21302b88d829c904ca3d99634bbfe808The ethics of early evidence - preparing for a possible breakthrough in Alzheimer's diseaseLowenthal, Justin; Hull, Sara Chandros; Pearson, Steven D.New England Journal of Medicine (2012), 367 (6), 488-490CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)There is no expanded citation for this reference.
- 272Takamatsu, K.; Takano, A.; Yakushiji, N.; Morishita, K.; Matsuura, N.; Makishima, M.; Ali, H. I.; Akaho, E.; Tai, A.; Sasaki, K.; Kakuta, H. Reduction of Lipophilicity at the Lipophilic Domain of RXR Agonists Enables Production of Subtype Preference: RXRa- Preferential Agonist Possessing a Sulfonamide Moiety. ChemMedChem 2008, 3 (3), 454– 460, DOI: 10.1002/cmdc.200700265[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlt1Krtbw%253D&md5=6487ff09cac2861d3877f8d6f8179aa2Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXRα-preferential agonist possessing a sulfonamide moietyTakamatsu, Kayo; Takano, Atsushi; Yakushiji, Nobumasa; Morishita, Ken-ichi; Matsuura, Nobuyasu; Makishima, Makoto; Ali, Hamed Ismail; Akaho, Eiichi; Tai, Akihiro; Sasaki, Kenji; Kakuta, HirokiChemMedChem (2008), 3 (3), 454-460CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Retinoid X receptor agonists (RXR agonists, rexinoids) are interesting candidates for the treatment of cancers such as tamoxifen-resistant breast cancer and taxol-resistant lung cancer. However, well-known RXR agonists possess a strong lipophilic character. In addn., although RXR has three subtypes, no subtype-selective RXR agonists are known. Thus the authors aimed to produce less-lipophilic and subtype-selective RXR agonists. By designing sulfonamide-type RXR agonists, compd. (I) was found to prefer RXRα over RXRβ and RXRγ, although the potency is less than the potencies of well-known RXR pan-agonists. Moreover, the results suggest that the redn. of lipophilicity at the hydrophobic interaction region of RXR agonists enables prodn. of RXR subtype preference. The finding will be useful for the creation of more potent and less-lipophilic subtype-selective RXR agonists aimed at the redn. of undesirable side effects.
- 273Boehm, M. F.; Zhang, L.; Zhi, L.; McClurg, M. R.; Berger, E.; Wagoner, M.; Mais, D. E.; Suto, C. M.; Davies, P. J. A.; Heyman, R. A.; Nadzan, A. M. Design and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia Cells. J. Med. Chem. 1995, 38 (16), 3146– 3155, DOI: 10.1021/jm00016a018[ACS Full Text], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmvF2htLg%253D&md5=c9bcc1f2449517cf62406151376cceddDesign and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia CellsBoehm, Marcus F.; Zhang, Lin; Zhi, Lin; McClurg, Michael R.; Berger, Elain; Wagoner, Murriel; Mais, Dale E.; Suto, Carla M.; Davies, Peter J. A.; et al.Journal of Medicinal Chemistry (1995), 38 (16), 3146-55CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structural modifications of the retinoid X receptor (RXR) selective compd. 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clin. trials for cancer and dermatol. indications, have resulted in the identification of increasingly potent retinoids with >1000-fold selectivity for the RXRs. The prepn. of a series of RXR selective retinoids as well as the biol. data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity are reported. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl]nicotinic acid (I, LG100268). This compd. has proven useful for investigating RXR-dependent biol. pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. These studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
- 274Takamatsu, K.; Takano, A.; Yakushiji, N.; Morohashi, K.; Morishita, K.; Matsuura, N.; Makishima, M.; Tai, A.; Sasaki, K.; Kakuta, H. The First Potent Subtype-Selective Retinoid X Receptor (RXR) Agonist Possessing a 3-Isopropoxy-4-isopropylphenylamino Moiety, NEt-3IP (RXRα/B-dual Agonist). ChemMedChem 2008, 3 (5), 780– 787, DOI: 10.1002/cmdc.200700313[Crossref], [PubMed], [CAS], Google Scholar275https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXms1emt7k%253D&md5=3ffe22aaa4a60aa23c7c3cb06da04a7cThe first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRα/β-dual agonist)Takamatsu, Kayo; Takano, Atsushi; Yakushiji, Nobumasa; Morohashi, Kazunori; Morishita, Kenichi; Matsuura, Nobuyasu; Makishima, Makoto; Tai, Akihiro; Sasaki, Kenji; Kakuta, HirokiChemMedChem (2008), 3 (5), 780-787CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Retinoid X receptor (RXR) agonists (rexinoids) are attracting much attention for their use in treatment of cancers, including tamoxifen-resistant breast cancer and taxol-resistant lung cancer, and metabolic disease. However, known RXR agonists have a highly lipophilic character. In addn., no subtype-selective RXR agonists have been found. The authors previously reported an RXRα-preferential agonist 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) amino]benzoic acid. The RXR agonistic activity is much less than that of well-known RXR agonists. To develop potent, less-lipophilic, and subtype-selective RXR agonists, the authors created new RXR agonists possessing alkoxy and iso-Pr groups as a lipophilic domain of the common structure of well-known RXR agonists. As a result, compds. possessing branched alkoxy groups (I) and (II), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, I was the first RXRα/β-selective (or RXRα/β-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP I is expected to become a new drug candidate and to be a useful biol. tool for clarifying each RXR subtype function.
- 275Pollinger, J.; Merk, D. Therapeutic Applications of the Versatile Fatty Acid Mimetic WY14643. Expert Opin. Ther. Pat. 2017, 27 (4), 517– 525, DOI: 10.1080/13543776.2017.1272578[Crossref], [PubMed], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFGhsbfO&md5=62cad45d760d76b2eb7b6ed1914a627bTherapeutic applications of the versatile fatty acid mimetic WY14643Pollinger, Julius; Merk, DanielExpert Opinion on Therapeutic Patents (2017), 27 (4), 517-525CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)A review. WY14643 - also known as pirinixic acid - is a versatile fatty acid mimetic that was originally developed as lipid lowering agent without knowledge of its mol. target. Various later studies discovered somewhat promiscuous activity of the compd. on several receptors and enzymes. Pirinixic acid though never having reached clin. use was subjected to many in vivo studies and exerted beneficial effects in a variety of disease models. Inventions claiming the use of WY14643 for numerous indications ranging from the originally intended application in metabolic dysbalances over cancer and inflammation to some rare syndromes have been evaluated. It is rather unlikely that pirinixic acid will gain relevance in treatment of metabolic diseases for which it was originally developed because more efficient and selective alternatives are available. Instead, several other claimed activities of the compd. e.g. in inflammation, neurodegeneration and cancer seem very promising. However, some of the underlying studies are biased and for some effects of pirinixic acid, the mol. target and mode of action remain to be identified.
- 276Watanabe, M.; Kakuta, H. Retinoid X Receptor Antagonists. Int. J. Mol. Sci. 2018, 19 (8), 2354 DOI: 10.3390/ijms19082354[Crossref], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnsVGiur4%253D&md5=89cdc1e936636de5b823f2da539c46e7Retinoid X receptor antagonistsWatanabe, Masaki; Kakuta, HirokiInternational Journal of Molecular Sciences (2018), 19 (8), 2354/1-2354/20CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)Retinoid X receptor (RXR) antagonists are not only useful as chem. tools for biol. research, but are also candidate drugs for the treatment of various diseases, including diabetes and allergies, although no RXR antagonist has yet been approved for clin. use. In this review, we present a brief overview of RXR structure, function, and target genes, and describe currently available RXR antagonists, their structural classification, and their evaluation, focusing on the latest research.
- 277Nakayama, M.; Yamada, S.; Ohsawa, F.; Ohta, Y.; Kawata, K.; Makishima, M.; Kakuta, H. Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB. ACS Med. Chem. Lett. 2011, 2 (12), 896– 900, DOI: 10.1021/ml200197e[ACS Full Text], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1Cqt77P&md5=2c88b7f5940b3763e4fe6708ce8bdc76Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IBNakayama, Mariko; Yamada, Shoya; Ohsawa, Fuminori; Ohta, Yui; Kawata, Kohei; Makishima, Makoto; Kakuta, HirokiACS Medicinal Chemistry Letters (2011), 2 (12), 896-900CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We discovered a potent retinoid X receptor (RXR) antagonist, 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(E)-styrylphenyl)amino]nicotinic acid (13e), that is structurally closely related to the RXR full agonist 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB) (4). Compd. 13e was synthesized via a simple route from 11 (I), a Me ester precursor of 4. Because 11 possesses high electrophilic reactivity because of the amino and alkoxy groups, it was readily transformed to 12 by iodization, and the iodine atom of 12 was converted to a C-C or C-N bond by means of palladium-catalyzed reaction to afford 13. Transcriptional activation assay revealed that 13g (in which the iodine atom was replaced with an amino group) is a weak RXR agonist, while 13d (a Ph group), 13e (a styryl group), and 13f (an anilino group) are RXR antagonists. Among them, 13e was found to be more potent than the known RXR antagonist PA452 (9).
- 278Merk, D.; Grisoni, F.; Friedrich, L.; Gelzinyte, E.; Schneider, G. Computer-Assisted Discovery of Retinoid X Receptor Modulating Natural Products and Isofunctional Mimetics. J. Med. Chem. 2018, 61 (12), 5442– 5447, DOI: 10.1021/acs.jmedchem.8b00494[ACS Full Text], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFWqt7zI&md5=7212ea553c1af55042265bf8862dc810Computer-Assisted Discovery of Retinoid X Receptor Modulating Natural Products and Isofunctional MimeticsMerk, Daniel; Grisoni, Francesca; Friedrich, Lukas; Gelzinyte, Elena; Schneider, GisbertJournal of Medicinal Chemistry (2018), 61 (12), 5442-5447CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Natural products (NPs) are progressively recognized as invaluable source of pharmacol. tools and lead structures. To enable NP-inspired retinoid X receptor (RXR) modulator design, three novel RXR-targeting NPs were computationally identified. Among them, valerenic acid was found to be selective for RXRβ, rendering it a unique pharmacol. tool compd. The NPs then served as templates for automated, ligand-based de novo design of innovative, easily accessible mimetics that inherited the biol. activities of their natural templates.
- 279Merk, D.; Grisoni, F.; Friedrich, L.; Gelzinyte, E.; Schneider, G. Scaffold Hopping from Synthetic RXR Modulators by Virtual Screening and de Novo Design. MedChemComm 2018, 9, 1289– 1292, DOI: 10.1039/C8MD00134K[Crossref], [PubMed], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVyjsrnO&md5=acb1eb5302706281d1c0ac7091a6b00bScaffold hopping from synthetic RXR modulators by virtual screening and de novo designMerk, Daniel; Grisoni, Francesca; Friedrich, Lukas; Gelzinyte, Elena; Schneider, GisbertMedChemComm (2018), 9 (8), 1289-1292CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)The lack of potent subtype-selective modulators of retinoid X receptors (RXRs) has hindered their full exploitation as promising drug targets. Using computational similarity searching, target prediction and automated de novo design, we identified novel RXR ligands exhibiting innovative mol. frameworks, pronounced receptor-subtype preference and suitable properties for hit-to-lead expansion.
- 280Pollinger, J.; Schierle, S.; Gellrich, L.; Ohrndorf, J.; Kaiser, A.; Heitel, P.; Chaikuad, A.; Knapp, S.; Merk, D. A Novel Biphenyl-Based Chemotype of Retinoid X Receptor Ligands Enables Subtype and Heterodimer Preferences. ACS Med. Chem. Lett. 2019, 10 (9), 1346– 1352, DOI: 10.1021/acsmedchemlett.9b00306[ACS Full Text], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFyrur%252FI&md5=68f55cb08fb121a37bbb61f3b2a7ff15A novel biphenyl-based chemotype of retinoid X receptor ligands enables subtype and heterodimer preferencesPollinger, Julius; Schierle, Simone; Gellrich, Leonie; Ohrndorf, Julia; Kaiser, Astrid; Heitel, Pascal; Chaikuad, Apirat; Knapp, Stefan; Merk, DanielACS Medicinal Chemistry Letters (2019), 10 (9), 1346-1352CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The nuclear retinoid X receptors (RXRs) are key ligand sensing transcription factors that serve as universal nuclear receptor heterodimer partners and are thus involved in numerous physiol. processes. Therapeutic targeting of RXRs holds high potential but available RXR activators suffer from limited safety. Selectivity for RXR subtypes or for certain RXR heterodimers are promising strategies for safer RXR modulation. Here, we report systematic structure-activity relationship studies on biphenyl carboxylates as new RXR ligand chemotype. We discovered specific structural modifications that enhance potency on RXRs, govern subtype preference, and vary modulation of different RXR heterodimers. Fusion of these structural motifs enabled specific tuning of subtype preferential profiles with markedly improved potency. Our results provide further evidence that RXR subtype selective ligands can be designed and present a novel chemotype of RXR modulators that can be tuned for subtype and heterodimer preferences.
- 281Islam, M. M.; Zhang, C.-L. TLX: A Master Regulator for Neural Stem Cell Maintenance and Neurogenesis. Biochim. Biophys. Acta, Gene Regul. Mech. 2015, 1849 (2), 210– 216, DOI: 10.1016/j.bbagrm.2014.06.001[Crossref], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Ohsr4%253D&md5=338813cbf592613401b5e0fd0171ea70TLX: A master regulator for neural stem cell maintenance and neurogenesisIslam, Mohammed M.; Zhang, Chun-LiBiochimica et Biophysica Acta, Gene Regulatory Mechanisms (2015), 1849 (2), 210-216CODEN: BBAGC6; ISSN:1874-9399. (Elsevier B.V.)A review. The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests that the misregulation of TLX might play a role in the onset and progression of human neurol. disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
- 282Shi, Y.; Lie, D. C.; Taupin, P.; Nakashima, K.; Ray, J.; Yu, R. T.; Gage, F. H.; Evans, R. M. Expression and Function of Orphan Nuclear Receptor TLX in Adult Neural Stem Cells. Nature 2004, 427 (6969), 78– 83, DOI: 10.1038/nature02211[Crossref], [PubMed], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhtVWhurrJ&md5=4ac248ea71ec56a6c9f43f53c09cc029Expression and function of orphan nuclear receptor TLX in adult neural stem cellsShi, Yanhong; Lie, D. Chichung; Taupin, Philippe; Nakashima, Kinichi; Ray, Jasodhara; Yu, Ruth T.; Gage, Fred H.; Evans, Ronald M.Nature (London, United Kingdom) (2004), 427 (6969), 78-83CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)The finding of neurogenesis in the adult brain led to the discovery of adult neural stem cells. TLX was initially identified as an orphan nuclear receptor expressed in vertebrate forebrains and is highly expressed in the adult brain. The brains of TLX-null mice have been reported to have no obvious defects during embryogenesis; however, mature mice suffer from retinopathies, severe limbic defects, aggressiveness, reduced copulation and progressively violent behavior. Here we show that TLX maintains adult neural stem cells in an undifferentiated, proliferative state. We show that TLX-expressing cells isolated by fluorescence-activated cell sorting (FACS) from adult brains can proliferate, self-renew and differentiate into all neural cell types in vitro. By contrast, TLX-null cells isolated from adult mutant brains fail to proliferate. Reintroducing TLX into FACS-sorted TLX-null cells rescues their ability to proliferate and to self-renew. In vivo, TLX mutant mice show a loss of cell proliferation and reduced labeling of nestin in neurogenic areas in the adult brain. TLX can silence glia-specific expression of the astrocyte marker GFAP in neural stem cells, suggesting that transcriptional repression may be crucial in maintaining the undifferentiated state of these cells.
- 283Miyawaki, T.; Uemura, A.; Dezawa, M.; Yu, R. T.; Ide, C.; Nishikawa, S.; Honda, Y.; Tanabe, Y.; Tanabe, T. Tlx, an Orphan Nuclear Receptor, Regulates Cell Numbers and Astrocyte Development in the Developing Retina. J. Neurosci. 2004, 24 (37), 8124– 8134, DOI: 10.1523/JNEUROSCI.2235-04.2004[Crossref], [PubMed], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXotVyisLg%253D&md5=37e674003cc27173173cff85cd071f68Tlx, an orphan nuclear receptor, regulates cell numbers and astrocyte development in the developing retinaMiyawaki, Takaya; Uemura, Akiyoshi; Dezawa, Mari; Yu, Ruth T.; Ide, Chizuka; Nishikawa, Shinichi; Honda, Yoshihito; Tanabe, Yasuto; Tanabe, TeruyoJournal of Neuroscience (2004), 24 (37), 8124-8134CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Tlx belongs to a class of orphan nuclear receptors that underlies many aspects of neural development in the CNS. However, the fundamental roles played by Tlx in the control of eye developmental programs remain elusive. By using Tlx knock-out (KO) mice, we show here that Tlx is expressed by retinal progenitor cells in the neuroblastic layer during the period of retinal layer formation, and it is crit. for controlling the generation of appropriate nos. of retinal progenies through the activities of cell cycle-related mols., cyclin D1 and p27Kip1. Tlx expression is restricted to Mueller cells in the mature retina and appears to control their proper development. Furthermore, we show that Tlx is expressed by immature astrocytes that migrate from the optic nerve onto the inner surface of the retina and is required for their generation and maturation, as assessed by honeycomb network formation and expression of R-cadherin, a crit. component for vasculogenesis. The impaired astrocyte network formation on the inner retinal surface is accompanied by the loss of vasculogenesis in Tlx KO retinas. Our studies thus indicate that Tlx underlies a fundamental developmental program of retinal organization and controls the generation of the proper nos. of retinal progenies and development of glial cells during the protracted period of retinogenesis.
- 284Monaghan, A. P.; Grau, E.; Bock, D.; Schütz, G. The Mouse Homolog of the Orphan Nuclear Receptor Tailless Is Expressed in the Developing Forebrain. Development 1995, 121 (3), 839– 853, DOI: 10.1242/dev.121.3.839[Crossref], [PubMed], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXksVCktLk%253D&md5=b30f03c84cbfbefe6204660259367032The mouse homolog of the orphan nuclear receptor tailless is expressed in the developing forebrainMonaghan, A. Paula; Grau, Evelyn; Bock, Dagmar; Schuetz, GuentherDevelopment (Cambridge, United Kingdom) (1995), 121 (3), 839-53CODEN: DEVPED; ISSN:0950-1991. (Company of Biologists)The Drosophila tailless gene is a member of the orphan nuclear receptor subfamily. In Drosophila, the tailless gene is required for pattern formation in embryonic poles. During development, tailless is activated in the termini of the embryo in response to the torso receptor tyrosine kinase signal transduction cascade. Recessive mutations of tailless result in abnormalities in anterior portions of the head and in all structures posterior to the eighth abdominal segment. Localized expression of tailless is required in combination with a second terminal gene, huckebein, to control the expression of downstream genes. The authors have isolated a mouse homolog of the Drosophila tailless gene, which shows considerable homol. in the DNA-binding domain suggesting that the resp. proteins bind similar recognition sequences. Although the ligand-binding domain shows features in common with the tailless ligand domain, it also shares conserved amino acid stretches with other orphan nuclear receptors, the human ovalbumin upstream binding protein transcription factors (hCOUP-TF I and II). The authors have analyzed the expression of tailless in mice, and show that it is specifically localized to the developing forebrain from day 8 p.c. and in dorsal midbrain from day 8.75 p.c. To define the anterior and posterior boundaries of expression, the authors compared the expression pattern of tailless to those of other forebrain markers, including distal-less (Dlx1), brain factor 1 (BF1), and the orthodenticle genes (Otx1 and Otx2). In addn. to the developing forebrain, these genes show dynamic patterns of expression in two structures whose development requires inductive signals from the forebrain: the eye and the nose. These results suggest that the mouse tailless gene may be required to pattern anterior brain differentiation.
- 285Li, S.; Sun, G.; Murai, K.; Ye, P.; Shi, Y. Characterization of TLX Expression in Neural Stem Cells and Progenitor Cells in Adult Brains. PLoS One 2012, 7 (8), e43324, DOI: 10.1371/journal.pone.0043324[Crossref], [PubMed], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlSjsrnI&md5=fc4b3d5642efc75c42ba30eb80277a39Characterization of TLX expression in neural stem cells and progenitor cells in adult brainsLi, Shengxiu; Sun, Guoqiang; Murai, Kiyohito; Ye, Peng; Shi, YanhongPLoS One (2012), 7 (8), e43324CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)TLX has been shown to play an important role in regulating the self-renewal and proliferation of neural stem cells in adult brains. However, the cellular distribution of endogenous TLX protein in adult brains remains to be elucidated. In this study, we used immunostaining with a TLX-specific antibody to show that TLX is expressed in both neural stem cells and transit-amplifying neural progenitor cells in the subventricular zone (SVZ) of adult mouse brains. Then, using a double thymidine analog labeling approach, we showed that almost all of the self-renewing neural stem cells expressed TLX. Interestingly, most of the TLX-pos. cells in the SVZ represented the thymidine analog-neg., relatively quiescent neural stem cell population. Using cell type markers and short-term BrdU labeling, we demonstrated that TLX was also expressed in the Mash1+ rapidly dividing type C cells. Furthermore, loss of TLX expression dramatically reduced BrdU label-retaining neural stem cells and the actively dividing neural progenitor cells in the SVZ, but substantially increased GFAP staining and extended GFAP processes. These results suggest that TLX is essential to maintain the self-renewing neural stem cells in the SVZ and that the GFAP+ cells in the SVZ lose neural stem cell property upon loss of TLX expression. Understanding the cellular distribution of TLX and its function in specific cell types may provide insights into the development of therapeutic tools for neurodegenerative diseases by targeting TLX in neural stem/progenitors cells.
- 286Benod, C.; Villagomez, R.; Webb, P. TLX: An Elusive Receptor. J. Steroid Biochem. Mol. Biol. 2016, 157, 41– 47, DOI: 10.1016/j.jsbmb.2015.11.001[Crossref], [PubMed], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVOqsb%252FP&md5=aec1c00da8a0e7d806852c6a223316baTLX: An elusive receptorBenod, Cindy; Villagomez, Rosa; Webb, PaulJournal of Steroid Biochemistry and Molecular Biology (2016), 157 (), 41-47CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)TLX (tailless receptor) is a member of the nuclear receptor superfamily and belongs to a class of nuclear receptors for which no endogenous or synthetic ligands have yet been identified. TLX is a promising therapeutic target in neurol. disorders and brain tumors. Thus, regulatory ligands for TLX need to be identified to complete the validation of TLX as a useful target and would serve as chem. probes to pursue the study of this receptor in disease models. It has recently been proved that TLX is druggable. However, to identify potent and specific TLX ligands with desirable biol. activity, a deeper understanding of where ligands bind, how they alter TLX conformation and of the mechanism by which TLX mediates the transcription of its target genes is needed. While TLX is in the process of escaping from orphanhood, future ligand design needs to progress in parallel with improved understanding of (i) the binding cavity or surfaces to target with small mols. on the TLX ligand binding domain and (ii) the nature of the TLX coregulators in particular cell and disease contexts. Both of these topics are discussed in this review.
- 287Yokoyama, A.; Takezawa, S.; Schule, R.; Kitagawa, H.; Kato, S. Transrepressive Function of TLX Requires the Histone Demethylase LSD1. Mol. Cell. Biol. 2008, 28 (12), 3995– 4003, DOI: 10.1128/MCB.02030-07[Crossref], [PubMed], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXntFanu74%253D&md5=a415eb96d627b7b5de33d2341ea578edTransrepressive function of TLX requires the histone demethylase LSD1Yokoyama, Atsushi; Takezawa, Shinichiro; Schule, Roland; Kitagawa, Hirochika; Kato, ShigeakiMolecular and Cellular Biology (2008), 28 (12), 3995-4003CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)TLX is an orphan nuclear receptor (also called NR2E1) that regulates the expression of target genes by functioning as a constitutive transrepressor. The physiol. significance of TLX in the cytodifferentiation of neural cells in the brain is known. However, the corepressors supporting the transrepressive function of TLX have yet to be identified. In this report, Y79 retinoblastoma cells were subjected to biochem. techniques to purify proteins that interact with TLX, and we identified LSD1 (also called KDM1), which appears to form a complex with CoREST and histone deacetylase 1. LSD1 interacted with TLX directly through its SWIRM and amine oxidase domains. LSD1 potentiated the transrepressive function of TLX through its histone demethylase activity as detd. by a luciferase assay using a genomically integrated reporter gene. LSD1 and TLX were recruited to a TLX-binding site in the PTEN gene promoter, accompanied by the demethylation of H3K4me2 and deacetylation of H3. Knockdown of either TLX or LSD1 derepressed expression of the endogenous PTEN gene and inhibited cell proliferation of Y79 cells. Thus, the present study suggests that LSD1 is a prime corepressor for TLX.
- 288Zhang, C.-L.; Zou, Y.; Yu, R. T.; Gage, F. H.; Evans, R. M. Nuclear Receptor TLX Prevents Retinal Dystrophy and Recruits the Corepressor Atrophin1. Genes Dev. 2006, 20 (10), 1308– 1320, DOI: 10.1101/gad.1413606[Crossref], [PubMed], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XltVyrtbk%253D&md5=29a9750b5ca0645efa9c27740e75f7e2Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin 1Zhang, Chun-Li; Zou, Yuhua; Yu, Ruth T.; Gage, Fred H.; Evans, Ronald M.Genes & Development (2006), 20 (10), 1308-1320CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)During mammalian embryogenesis, precise coordination of progenitor cell proliferation and differentiation is essential for proper organ size and function. The involvement of TLX (NR2E1), an orphan nuclear receptor, has been implicated in ocular development, as Tlx-/- mice exhibit visual impairment. Using genetic and biochem. approaches, we show that TLX modulates retinal progenitor cell proliferation and cell cycle re-entry by directly regulating the expression of Pten and its target cyclin D1. Addnl., TLX finely tunes the progenitor differentiation program by modulating the phospholipase C and mitogen-activated protein kinase (MAPK) pathways and the expression of an array of cell type-specific transcriptional regulators. Consequently, Tlx-/- mice have a dramatic redn. in retina thickness and enhanced generation of S-cones, and develop severe early onset retinal dystrophy. Furthermore, TLX interacts with atrophin 1 (Atn1), a corepressor that is involved in human neurodegenerative dentatorubral-pallidoluysian atrophy (DRPLA) and that is essential for development of multiple tissues. Together, these results reveal a mol. strategy by which an orphan nuclear receptor can precisely orchestrate tissue-specific proliferation and differentiation programs to prevent retinal malformation and degeneration.
- 289Estruch, S. B.; Buzón, V.; Carbó, L. R.; Schorova, L.; Lüders, J.; Estébanez-Perpiñá, E. The Oncoprotein BCL11A Binds to Orphan Nuclear Receptor TLX and Potentiates Its Transrepressive Function. PLoS One 2012, 7 (6), e37963, DOI: 10.1371/journal.pone.0037963[Crossref], [PubMed], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xos1ekt7o%253D&md5=aad222b770759704e8190a3a581e75e1The oncoprotein BCL11A binds to orphan nuclear receptor TLX and potentiates its transrepressive functionEstruch, Sara B.; Buzon, Victor; Carbo, Laia R.; Schorova, Lenka; Luders, Jens; Estebanez-Perpina, EvaPLoS One (2012), 7 (6), e37963CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Nuclear orphan receptor TLX (NR2E1) functions primarily as a transcriptional repressor and its pivotal role in brain development, glioblastoma, mental retardation and retinopathologies make it an attractive drug target. TLX is expressed in the neural stem cells (NSCs) of the subventricular zone and the hippocampus subgranular zone, regions with persistent neurogenesis in the adult brain, and functions as an essential regulator of NSCs maintenance and self-renewal. Little is known about the TLX social network of interactors and only few TLX coregulators are described. To identify and characterize novel TLX-binders and possible coregulators, we performed yeast-two-hybrid (Y2H) screens of a human adult brain cDNA library using different TLX constructs as baits. Our screens identified multiple clones of Atrophin-1 (ATN1), a previously described TLX interactor. In addn., we identified an interaction with the oncoprotein and zinc finger transcription factor BCL11A (CTIP1/Evi9), a key player in the hematopoietic system and in major blood-related malignancies. This interaction was validated by expression and coimmunopptn. in human cells. BCL11A potentiated the transrepressive function of TLX in an in vitro reporter gene assay. Our work suggests that BCL11A is a novel TLX coregulator that might be involved in TLX-dependent gene regulation in the brain.
- 290Sun, G.; Yu, R. T.; Evans, R. M.; Shi, Y. Orphan Nuclear Receptor TLX Recruits Histone Deacetylases to Repress Transcription and Regulate Neural Stem Cell Proliferation. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (39), 15282– 15287, DOI: 10.1073/pnas.0704089104[Crossref], [PubMed], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFWkurnK&md5=ad0573103a07c12737303107ce39df85Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferationSun, GuoQiang; Yu, Ruth T.; Evans, Ronald M.; Shi, YanhongProceedings of the National Academy of Sciences of the United States of America (2007), 104 (39), 15282-15287CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)TLX is a transcription factor that is essential for neural stem cell proliferation and self-renewal. However, the mol. mechanism of TLX-mediated neural stem cell proliferation and self-renewal is largely unknown. We show here that TLX recruits histone deacetylases (HDACs) to its downstream target genes to repress their transcription, which in turn regulates neural stem cell proliferation. TLX interacts with HDAC3 and HDAC5 in neural stem cells. The HDAC5-interaction domain was mapped to TLX residues 359-385, which contains a conserved nuclear receptor-coregulator interaction motif IXXLL. Both HDAC3 and HDAC5 have been shown to be recruited to the promoters of TLX target genes along with TLX in neural stem cells. Recruitment of HDACs led to transcriptional repression of TLX target genes, the cyclin-dependent kinase inhibitor, p21CIP1/WAF1(p21), and the tumor suppressor gene, pten. Either inhibition of HDAC activity or knockdown of HDAC expression led to marked induction of p21 and pten gene expression and dramatically reduced neural stem cell proliferation, suggesting that the TLX-interacting HDACs play an important role in neural stem cell proliferation. Moreover, expression of a TLX peptide contg. the minimal HDAC5 interaction domain disrupted the TLX-HDAC5 interaction. Disruption of this interaction led to significant induction of p21 and pten gene expression and to dramatic inhibition of neural stem cell proliferation. Taken together, these findings demonstrate a mechanism for neural stem cell proliferation through transcriptional repression of p21 and pten gene expression by TLX-HDAC interactions.
- 291Griffett, K.; Bedia-Diaz, G.; Hegazy, L.; de Vera, I. M. S.; Wanninayake, U. S.; Billon, C.; Koelblen, T.; Wilhelm, M. L.; Burris, T. P. The Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural Retinoids. Cell Chem. Biol. 2020, 27 (10), 1272– 1284, DOI: 10.1016/j.chembiol.2020.07.013[Crossref], [PubMed], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFGhtL7F&md5=1d97202ab3dca443b5c8c7fcf36ef13eThe Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural RetinoidsGriffett, Kristine; Bedia-Diaz, Gonzalo; Hegazy, Lamees; de Vera, Ian Mitchelle S.; Wanninayake, Udayanga S.; Billon, Cyrielle; Koelblen, Thomas; Wilhelm, McKenna L.; Burris, Thomas P.Cell Chemical Biology (2020), 27 (10), 1272-1284.e4CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)TLX is an orphan nuclear receptor that plays a crit. role in both embryonic and adult neurogenesis, as well in the pathogenesis of glioblastomas. TLX functions predominately as a transcriptional repressor, but no natural ligands or high-affinity synthetic ligands have been identified. Here, we describe the identification of natural and synthetic retinoids as functional ligands for TLX. We identified potent synthetic retinoids that directly bind to TLX and either activate or inhibit its transcriptional repressor activity. Furthermore, we identified all-trans and 11-cis retinaldehyde (retinal), retinoids that play an essential role in the visual cycle, as the preferential natural retinoids that bind to and modulate the function of TLX. Mol. dynamics simulations followed by mutational anal. provided insight into the mol. basis of retinoid binding to TLX. Our data support the validity of TLX as a target for development of therapeutics to treat cognitive disorders and/or glioblastomas.
- 292Benod, C.; Villagomez, R.; Filgueira, C. S.; Hwang, P. K.; Leonard, P. G.; Poncet-Montange, G.; Rajagopalan, S.; Fletterick, R. J.; Gustafsson, J.-Å.; Webb, P. The Human Orphan Nuclear Receptor Tailless (TLX, NR2E1) Is Druggable. PLoS One 2014, 9 (6), e99440, DOI: 10.1371/journal.pone.0099440[Crossref], [PubMed], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1antLzN&md5=2627261362125e6ad548c7aa5b2a1802The human orphan nuclear receptor tailless (TLX, NR2E1) is druggableBenod, Cindy; Villagomez, Rosa; Filgueira, Carly S.; Hwang, Peter K.; Leonard, Paul G.; Poncet-Montange, Guillaume; Rajagopalan, Senapathy; Fletterick, Robert J.; Gustafsson, Jan-Ake; Webb, PaulPLoS One (2014), 9 (6), e99440/1-e99440/13, 13 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Nuclear receptors (NRs) are an important group of ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of orphan NRs. Small mols. to target these orphan NRs will provide unique resources for uncovering regulatory systems that impact human health and to modulate these pathways with drugs. The orphan NR tailless (TLX, NR2E1), a transcriptional repressor, is a major player in neurogenesis and Neural Stem Cell (NSC) derived brain tumors. No chem. probes that modulate TLX activity are available, and it is not clear whether TLX is druggable. To assess TLX ligand binding capacity, we created homol. models of the TLX ligand binding domain (LBD). Results suggest that TLX belongs to an emerging class of NRs that lack LBD helixes α1 and α2 and that it has potential to form a large open ligand binding pocket (LBP). Using a medium throughput screening strategy, we investigated direct binding of 20,000 compds. to purified human TLX protein and verified interactions with a secondary (orthogonal) assay. We then assessed effects of verified binders on TLX activity using luciferase assays. As a result, we report identification of three compds. (ccrp1, ccrp2 and ccrp3) that bind to recombinant TLX protein with affinities in the high nanomolar to low micromolar range and enhance TLX transcriptional repressive activity. We conclude that TLX is druggable and propose that our lead compds. could serve as scaffolds to derive more potent ligands. While our ligands potentiate TLX repressive activity, the question of whether it is possible to develop ligands to de-repress TLX activity remains open.
- 293Zhi, X.; Zhou, X. E.; He, Y.; Searose-Xu, K.; Zhang, C.-L.; Tsai, C.-C.; Melcher, K.; Xu, H. E. Structural Basis for Corepressor Assembly by the Orphan Nuclear Receptor TLX. Genes Dev. 2015, 29 (4), 440– 450, DOI: 10.1101/gad.254904.114[Crossref], [PubMed], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkt1Sqt7g%253D&md5=b9d3267b46d4936a660860161f542160Structural basis for corepressor assembly by the orphan nuclear receptor TLXZhi, Xiaoyong; Zhou, X. Edward; He, Yuanzheng; Searose-Xu, Kelvin; Zhang, Chun-Li; Tsai, Chih-Cheng; Melcher, Karsten; Xu, H. EricGenes & Development (2015), 29 (4), 440-450CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conserved ALXXLXXY motif of the Atro box. Mutations that weaken the TLX-Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression.
- 294Tan, M. H. E.; Zhou, X. E.; Soon, F.-F.; Li, X.; Li, J.; Yong, E.-L.; Melcher, K.; Xu, H. E. The Crystal Structure of the Orphan Nuclear Receptor NR2E3/PNR Ligand Binding Domain Reveals a Dimeric Auto-Repressed Conformation. PLoS One 2013, 8 (9), e74359, DOI: 10.1371/journal.pone.0074359[Crossref], [PubMed], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsV2rurnK&md5=9add629d6a8e857eec883b8a5194b786The crystal structure of the orphan nuclear receptor NR2E3/PNR ligand binding domain reveals a dimeric auto-repressed conformationTan, M. H. Eileen; Zhou, X. Edward; Soon, Fen-Fen; Li, Xiaodan; Li, Jun; Yong, Eu-Leong; Melcher, Karsten; Xu, H. EricPLoS One (2013), 8 (9), e74359CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Photoreceptor-specific nuclear receptor (PNR, NR2E3) is a key transcriptional regulator of human photoreceptor differentiation and maintenance. Mutations in the NR2E3-encoding gene cause various retinal degenerations, including Enhanced S-cone syndrome, retinitis pigmentosa and Goldman-Favre disease. Although physiol. ligands have not been identified, it is believed that binding of small mol. agonists, receptor desumoylation and receptor heterodimerization may switch NR2E3 from a transcriptional repressor to an activator. While these features make NR2E3 a potential therapeutic target for the treatment of retinal diseases, there has been a clear lack of structural information for the receptor. Here, we report the crystal structure of the apo NR2E3 ligand binding domain (LBD) at 2.8 Å resoln. Apo NR2E3 functions as transcriptional repressor in cells and the structure of its LBD is in a dimeric auto-repressed conformation. In this conformation, the putative ligand binding pocket is filled with bulky hydrophobic residues and the activation-function-2 (AF2) helix occupies the canonical cofactor binding site. Mutations designed to disrupt either the AF2/cofactor-binding site interface or the dimer interface compromised the transcriptional repressor activity of this receptor. Together, these results reveal several conserved structural features shared by related orphan nuclear receptors, suggest that most disease-causing mutations affect the receptor's structural integrity and allowed us to model a putative active conformation that can accommodate small ligands in its pocket.
- 295Sablin, E. P.; Woods, A.; Krylova, I. N.; Hwang, P.; Ingraham, H. A.; Fletterick, R. J. The Structure of Corepressor Dax-1 Bound to Its Target Nuclear Receptor LRH-1. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (47), 18390– 18395, DOI: 10.1073/pnas.0808936105[Crossref], [PubMed], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVyhsrvJ&md5=a3c7dad13cfc5c9cc5d02e7fdded57d2The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1Sablin, Elena P.; Woods, April; Krylova, Irina N.; Hwang, Peter; Ingraham, Holly A.; Fletterick, Robert J.Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (47), 18390-18395, S18390/1-S18390/11CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The Dax-1 protein is an enigmatic nuclear receptor that lacks an expected DNA binding domain, yet functions as a potent corepressor of nuclear receptors. Here we report the structure of Dax-1 bound to one of its targets, liver receptor homolog 1 (LRH-1). Unexpectedly, Dax-1 binds to LRH-1 using a new module, a repressor helix built from a family conserved sequence motif, PCFXXLP. Mutations in this repressor helix that are linked with human endocrine disorders dissoc. the complex and attenuate Dax-1 function. The structure of the Dax-1:LRH-1 complex provides the mol. mechanism for the function of Dax-1 as a potent transcriptional repressor.
- 296Kandel, P.; Semerci, F.; Bajic, A.; Baluya, D.; Ma, L.; Chen, K.; Cao, A.; Phongmekhin, T.; Matinyan, N.; Choi, W.; Jiménez-Panizo, A.; Chamakuri, S.; Raji, I. O.; Chang, L.; Fuentes-Prior, P.; MacKenzie, K. R.; Benn, C. L.; Estébanez-Perpiñá, E.; Venken, K.; Moore, D. D.; Young, D. W.; Maletic-Savatic, M. Oleic Acid Triggers Hippocampal Neurogenesis by Binding to TLX/NR2E1. bioRxiv 2020, 2020.10.28.359810.
- 297Niu, W.; Zou, Y.; Shen, C.; Zhang, C.-L. Activation of Postnatal Neural Stem Cells Requires Nuclear Receptor TLX. J. Neurosci. 2011, 31 (39), 13816– 13828, DOI: 10.1523/JNEUROSCI.1038-11.2011[Crossref], [PubMed], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1ylu7rK&md5=7b1a575f1e1e085a288184f30482fa49Activation of postnatal neural stem cells requires nuclear receptor TLXNiu, Wenze; Zou, Yuhua; Shen, Cheng Cheng; Zhang, Chun-LiJournal of Neuroscience (2011), 31 (39), 13816-13828CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Neural stem cells (NSCs) continually produce new neurons in postnatal brains. However, the majority of these cells stay in a nondividing, inactive state. The mol. mechanism that is required for these cells to enter proliferation still remains largely unknown. Here, we show that nuclear receptor TLX (NR2E1) controls the activation status of postnatal NSCs in mice. Lineage tracing indicates that TLX-expressing cells give rise to both activated and inactive postnatal NSCs. Surprisingly, loss of TLX function does not result in spontaneous glial differentiation, but rather leads to a precipitous age-dependent increase of inactive cells with marker expression and radial morphol. for NSCs. These inactive cells are mispositioned throughout the granular cell layer of the dentate gyrus during development and can proliferate again after reintroduction of ectopic TLX. RNA-seq anal. of sorted NSCs revealed a TLX-dependent global expression signature, which includes the p53 signaling pathway. TLX regulates p21 expression in a p53-dependent manner, and acute removal of p53 can rescue the proliferation defect of TLX-null NSCs in culture. Together, these findings suggest that TLX acts as an essential regulator that ensures the proliferative ability of postnatal NSCs by controlling their activation through genetic interaction with p53 and other signaling pathways.
- 298Roy, K.; Kuznicki, K.; Wu, Q.; Sun, Z.; Bock, D.; Schutz, G.; Vranich, N.; Monaghan, A. P. The Tlx Gene Regulates the Timing of Neurogenesis in the Cortex. J. Neurosci. 2004, 24 (38), 8333– 8345, DOI: 10.1523/JNEUROSCI.1148-04.2004[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXotVyntLs%253D&md5=471431a11f3d96864a26644032d68a65The tlx gene regulates the timing of neurogenesis in the cortexRoy, Kristine; Kuznicki, Kathleen; Wu, Qiang; Sun, Zhuoxin; Bock, Dagmar; Schutz, Gunther; Vranich, Nancy; Monaghan, A. PaulaJournal of Neuroscience (2004), 24 (38), 8333-8345CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)The tailless (tlx) gene is a forebrain-restricted transcription factor. Tlx mutant animals exhibit a redn. in the size of the cerebral hemispheres and assocd. structures (Monaghan et al., 1997). Superficial cortical layers are specifically reduced, whereas deep layers are relatively unaltered (Land and Monaghan, 2003). To det. whether the adult laminar phenotype has a developmental etiol. and whether it is assocd. with a change in proliferation/differentiation decisions, we examd. the cell cycle and neurogenesis in the embryonic cortex. We found that there is a temporal and regional requirement for the Tlx protein in progenitor cells (PCs). Neurons prematurely differentiate at all rostrocaudal levels up to mid-neurogenesis in mutant animals. Heterozygote animals have an intermediate phenotype indicating there is a threshold requirement for Tlx in early cortical neurogenesis. Our studies indicate that PCs in the ventricular zone are sensitive to loss of Tlx in caudal regions only; however, PCs in the subventricular zone are altered at all rostrocaudal levels in tlx-deficient animals. Furthermore, we found that the cell cycle is shorter from embryonic day 9.5 in tlx-/- embryos. At mid-neurogenesis, the PC population becomes depleted, and late PCs have a longer cell cycle in tlx-deficient animals. Consequently, later generated structures, such as upper cortical layers, the dentate gyrus, and the olfactory bulbs, are severely reduced. These studies indicate that tlx is an essential intrinsic regulator in the decision to proliferate or differentiate in the developing forebrain.
- 299Shi, Y.; Sun, G.; Zhao, C.; Stewart, R. Neural Stem Cell Self-Renewal. Crit. Rev. Oncol. Hematol. 2008, 65 (1), 43– 53, DOI: 10.1016/j.critrevonc.2007.06.004[Crossref], [PubMed], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sjjt1CrtA%253D%253D&md5=62802c2db4d67b0d36d5a4a3e1cf1523Neural stem cell self-renewalShi Yanhong; Sun Guoqiang; Zhao Chunnian; Stewart RichardCritical reviews in oncology/hematology (2008), 65 (1), 43-53 ISSN:1040-8428.Two fundamental properties of stem cells are their ability to self-renew and to differentiate. Self-renewal is an integration of proliferation control with the maintenance of an undifferentiated state. Stem cell self-renewal is regulated by the dynamic interplay between transcription factors, epigenetic control, microRNA (miRNA) regulators, and cell-extrinsic signals from the microenvironment in which stem cells reside. Recent progress in defining specific roles for cell-intrinsic factors and extrinsic factors in regulating stem cell self-renewal starts to unfold the multilayered regulatory networks. This review focuses on cell-intrinsic regulators, including orphan nuclear receptor TLX, polycomb transcriptional repressor Bmi1, high-mobility-group DNA binding protein Sox2, basic helix-loop-helix Hes genes, histone modifying enzymes and chromatin remodeling proteins, and small RNA modulators, as well as cell-extrinsic signaling molecules, such as Wnt, Notch, Sonic hedgehog (Shh), TGFalpha, EGF, and FGF. Unraveling the mechanisms by which neural stem cells renew themselves will provide insights into both basic neurosciences and clinical applications of stem cell-based cell replacement therapies for neurodegenerative diseases.
- 300Elmi, M.; Matsumoto, Y.; Zeng, Z.; Lakshminarasimhan, P.; Yang, W.; Uemura, A.; Nishikawa, S.; Moshiri, A.; Tajima, N.; Agren, H.; Funa, K. TLX Activates MASH1 for Induction of Neuronal Lineage Commitment of Adult Hippocampal Neuroprogenitors. Mol. Cell. Neurosci. 2010, 45 (2), 121– 131, DOI: 10.1016/j.mcn.2010.06.003[Crossref], [PubMed], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVeht73K&md5=473e32be30770e18f63cb5af546be14bTLX activates MASH1 for induction of neuronal lineage commitment of adult hippocampal neuroprogenitorsElmi, Muna; Matsumoto, Yoshiki; Zeng, Zhao-jun; Lakshminarasimhan, Pavithra; Yang, Weiwen; Uemura, Akiyoshi; Nishikawa, Shin-ichi; Moshiri, Alicia; Tajima, Nobuyoshi; Aagren, Hans; Funa, KeikoMolecular and Cellular Neuroscience (2010), 45 (2), 121-131CODEN: MOCNED; ISSN:1044-7431. (Elsevier B.V.)The orphan nuclear receptor TLX has been proposed to act as a repressor of cell cycle inhibitors to maintain the neural stem cells in an undifferentiated state, and prevents commitment into astrocyte lineages. However, little is known about the mechanism of TLX in neuronal lineage commitment and differentiation. A majority of adult rat hippocampus-derived progenitors (AHPs) cultured in the presence of FGF express a high level of TLX and a fraction of these cells also express the proneural gene MASH1. Upon FGF withdrawal, TLX rapidly decreased, while MASH1 was intensely expressed within 1 h, decreasing gradually to disappear at 24 h. Adenoviral transduction of TLX in AHP cells in the absence of FGF transiently increased cell proliferation, however, later resulted in neuronal differentiation by inducing MASH1, Neurogenin1, DCX, and MAP2ab. Furthermore, TLX directly targets and activates the MASH1 promoter through interaction with Sp1, recruiting co-activators whereas dismissing the co-repressor HDAC4. Conversely, silencing of TLX in AHPs decreased β-III tubulin and DCX expression and promoted glial differentiation. Our results thus suggest that TLX not only acts as a repressor of cell cycle and glial differentiation but also activates neuronal lineage commitment in AHPs.
- 301Liu, H.-K.; Belz, T.; Bock, D.; Takacs, A.; Wu, H.; Lichter, P.; Chai, M.; Schütz, G. The Nuclear Receptor Tailless Is Required for Neurogenesis in the Adult Subventricular Zone. Genes Dev. 2008, 22 (18), 2473– 2478, DOI: 10.1101/gad.479308[Crossref], [PubMed], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1ClsbjO&md5=2ef11ad47ec1b056f811bef13ca816f4The nuclear receptor tailless is required for neurogenesis in the adult subventricular zoneLiu, Hai-Kun; Belz, Thorsten; Bock, Dagmar; Takacs, Andrea; Wu, Hui; Lichter, Peter; Chai, Minqiang; Schuetz, GuentherGenes & Development (2008), 22 (18), 2473-2478CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)The tailless (Tlx) gene encodes an orphan nuclear receptor that is expressed by neural stem/progenitor cells in the adult brain of the subventricular zone (SVZ) and the dentate gyrus (DG). The function of Tlx in neural stem cells of the adult SVZ remains largely unknown. We show here that in the SVZ of the adult brain Tlx is exclusively expressed in astrocyte-like B cells. An inducible mutation of the Tlx gene in the adult brain leads to complete loss of SVZ neurogenesis. Furthermore, anal. indicates that Tlx is required for the transition from radial glial cells to astrocyte-like neural stem cells. These findings demonstrate the crucial role of Tlx in the generation and maintenance of NSCs in the adult SVZ in vivo.
- 302Monaghan, A. P.; Bock, D.; Gass, P.; Schwger, A.; Wolfer, D. P.; Lipp, H.-P.; Schütz, G. Defective Limbic System in Mice Lacking the Tailless Gene. Nature 1997, 390 (6659), 515– 517, DOI: 10.1038/37364[Crossref], [PubMed], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXnvF2nsrY%253D&md5=b67b720676987ff4c0fa44f5c9a530d8Defective limbic system in mice lacking the tailless geneMonaghan, A. P.; Bock, D.; Gass, P.; Schwager, A.; Wolfer, D. P.; Lipp, H.-P.; Schhutz, G.Nature (London) (1997), 390 (6659), 515-517CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)The gene tailless is a member of the superfamily of genes that encode transcription factors of the ligand-activated nuclear receptor type, and is expressed in the invertebrate and vertebrate brain. In mice, it transcripts are restricted to the periventricular zone of the forebrain, the site or origin of neurons and glia. Here we use homologous recombination to generate mice that lack a functional tailless protein. Homozygous mutant mice are viable at birth, indicating that tailless is not required for prenatal survival; however, adult mutant mice show a redn. in the size of rhinencephalic and limbic structures, including the olfactory infrarhinal and entorhinal cortex, amygdala and dentate gyrus. Both male and female mice are more aggressive than usual and females lack normal maternal instincts. These animals therefore enable a mol. approach to be taken towards understanding the genetic architecture and morphogenesis of the forebrain.
- 303Yu, R. T.; Chiang, M.-Y.; Tanabe, T.; Kobayashi, M.; Yasuda, K.; Evans, R. M.; Umesono, K. The Orphan Nuclear Receptor Tlx Regulates Pax2 and Is Essential for Vision. Proc. Natl. Acad. Sci. U. S. A. 2000, 97 (6), 2621– 2625, DOI: 10.1073/pnas.050566897[Crossref], [PubMed], [CAS], Google Scholar307https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXitVaiu7k%253D&md5=0f0f465d337c9b00400131713e1622c9The orphan nuclear receptor Tlx regulates Pax2 and is essential for visionYu, Ruth T.; Chiang, Ming-Yi; Tanabe, Teruyo; Kobayashi, Mime; Yasuda, Kunio; Evans, Ronald M.; Umesono, KazuhikoProceedings of the National Academy of Sciences of the United States of America (2000), 97 (6), 2621-2625CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Although the development of the vertebrate eye is well described, the no. of transcription factors known to be key to this process is still limited. The localized expression of the orphan nuclear receptor Tlx in the optic cup and discrete parts of the central nervous system suggested the possible role of Tlx in the formation or function of these structures. Analyses of Tlx targeted mice revealed that, in addn. to the central nervous system cortical defects, lack of Tlx function results in progressive retinal and optic nerve degeneration with assocd. blindness. An extensive screen of Tlx-pos. and Tlx-neg. P19 neural precursors identified Pax2 as a candidate target gene. This identification is significant, because Pax2 is known to be involved in retinal development in both the human and the mouse eye. We find that Pax2 is a direct target and that the Tlx binding site in its promoter is conserved between mouse and human. These studies show that Tlx is a key component of retinal development and vision and an upstream regulator of the Pax2 signaling cascade.
- 304Juárez, P.; Valdovinos, M. G.; May, M. E.; Lloyd, B. P.; Couppis, M. H.; Kennedy, C. H. Serotonin2A/C Receptors Mediate the Aggressive Phenotype of TLX Gene Knockout Mice. Behav. Brain Res. 2013, 256, 354– 361, DOI: 10.1016/j.bbr.2013.07.044[Crossref], [PubMed], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsleiurzM&md5=bb753288cca15b41caf69ddd7da1c1c9Serotonin2A/C receptors mediate the aggressive phenotype of TLX gene knockout miceJuarez, Pablo; Valdovinos, Maria G.; May, Michael E.; Lloyd, Blair P.; Couppis, Maria H.; Kennedy, Craig H.Behavioural Brain Research (2013), 256 (), 354-361CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)Deleting the tailless TLX gene in mice produces a highly aggressive phenotype yet to be characterized in terms of heterozygous animals or neurotransmitter mechanisms. We sought to establish pharmacol. control over aggression and study the role of serotonin 5-HT 2A/C receptors in mediating changes in aggression. We analyzed aggression in mice heterozygous +/- or homozygous -/- for the TLX gene and wild-types +/+ using a resident-intruder paradigm. No +/+ mice were aggressive, 36 fx of +/- TLX and 100 fx of -/- TLX mice showed aggression. Dose-effect functions were established for clozapine 0.1-1.5 mg/kg, i.p., ketanserin 0.3-1.25 mg/kg, i.p., and ±-1-2,5-dimethoxy-4-iodophenyl-2-aminopropane ± DOI| 0.5-2.0 mg/kg, i.p. Injecting clozapine decreased the frequency and duration of attacks for +/- TLX and -/- TLX mice. Clozapine did not decrease grooming in either +/- TLX or -/- TLX mice but may have increased locomotion for -/- TLX mice. Injecting ketanserin, a 5-HT2A/C receptor antagonist, produced differential decreases in frequency and latency to aggression between genotypes and corresponding increases in locomotor behavior. Injecting ± DOI, a 5-HT2A/C receptor agonist, increased the frequency and duration of attacks, decreased the latency to attacks, and decreased locomotion in +/- and -/- TLX mice. Results of the current study suggest aggression displayed by TLX null and heterozygous mice involves 5-HT2A/C receptors.
- 305Murai, K.; Qu, Q.; Sun, G.; Ye, P.; Li, W.; Asuelime, G.; Sun, E.; Tsai, G. E.; Shi, Y. Nuclear Receptor TLX Stimulates Hippocampal Neurogenesis and Enhances Learning and Memory in a Transgenic Mouse Model. Proc. Natl. Acad. Sci. U. S. A. 2014, 111 (25), 9115– 9120, DOI: 10.1073/pnas.1406779111[Crossref], [PubMed], [CAS], Google Scholar309https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpsVKjt7s%253D&md5=3e1045115a97490d8ad5341273468df8Nuclear receptor TLX stimulates hippocampal neurogenesis and enhances learning and memory in a transgenic mouse modelMurai, Kiyohito; Qu, Qiuhao; Sun, GuoQiang; Ye, Peng; Li, Wendong; Asuelime, Grace; Sun, Emily; Tsai, Guochuan E.; Shi, YanhongProceedings of the National Academy of Sciences of the United States of America (2014), 111 (25), 9115-9120CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased nos. of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the nos. of BrdU+ cells and BrdU+NeuN+ neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong assocn. between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory.
- 306O’Leary, J. D.; Kozareva, D. A.; Hueston, C. M.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. The Nuclear Receptor Tlx Regulates Motor, Cognitive and Anxiety-Related Behaviours during Adolescence and Adulthood. Behav. Brain Res. 2016, 306, 36– 47, DOI: 10.1016/j.bbr.2016.03.022[Crossref], [PubMed], [CAS], Google Scholar310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xks1yiurw%253D&md5=1b9ec138b713c67c7ffa7cb2f09b24d8The nuclear receptor Tlx regulates motor, cognitive and anxiety-related behaviours during adolescence and adulthoodO'Leary, James D.; Kozareva, Danka A.; Hueston, Cara M.; O'Leary, Olivia F.; Cryan, John F.; Nolan, Yvonne M.Behavioural Brain Research (2016), 306 (), 36-47CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)The nuclear receptor Tlx is a key regulator of embryonic and adult hippocampal neurogenesis and has been genetically linked to bipolar disorder. Mice lacking Tlx (Nr2e1-/-) display deficits in adult hippocampal neurogenesis and behavioral abnormalities. However, whether Tlx regulates behavior during adolescence or in a sex-dependent manner remains unexplored. Therefore, we investigated the role of Tlx in a series of behavioral tasks in adolescent male and female mice with a spontaneous deletion of Tlx (Nr2e1-/- mice). Testing commenced at adolescence (postnatal day 28) and continued until adulthood (postnatal day 67). Adolescent male and female Nr2e1-/- mice were hyperactive in an open field, an effect that persisted in adulthood. Male but not female Nr2e1-/- mice exhibited reduced thigmotaxis during adolescence and adulthood. Impairments in rotarod motor performance developed in male and female Nr2e1-/- mice at the onset of adulthood. Spontaneous alternation in the Y-maze, a hippocampus-dependent task, was impaired in adolescent but not adult male and female Nr2e1-/- mice. Contextual fear conditioning was impaired in adolescent male Nr2e1-/- mice only, but both male and female adolescent Nr2e1-/- mice showed impaired cued fear conditioning, a hippocampal-amygdala dependent cognitive process. These deficits persisted into adulthood in males but not females. In conclusion, deletion of Tlx impairs motor, cognitive and anxiety-related behaviors during adolescence and adulthood in male and female mice with most effects occurring during adolescence rather than adulthood, independent of housing conditions. This suggests that Tlx has functions beyond regulation of adult hippocampal neurogenesis, and may be an important target in understanding neurobiol. disorders.
- 307Kozareva, D. A.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. Deletion of TLX and Social Isolation Impairs Exercise-Induced Neurogenesis in the Adolescent Hippocampus. Hippocampus 2018, 28 (1), 3– 11, DOI: 10.1002/hipo.22805[Crossref], [PubMed], [CAS], Google Scholar311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Sitw%253D%253D&md5=1d99b0ba3b31824e2449ecdfcedf7b4bDeletion of TLX and social isolation impairs exercise-induced neurogenesis in the adolescent hippocampusKozareva, Danka A.; O'Leary, Olivia F.; Cryan, John F.; Nolan, Yvonne M.Hippocampus (2018), 28 (1), 3-11CODEN: HIPPEL; ISSN:1050-9631. (Wiley-Blackwell)Adolescence is a sensitive period of neurodevelopment during which life experiences can have profound effects on the brain. Hippocampal neurogenesis, the neurodevelopmental process of generating functional new neurons from neural stem cells, occurs throughout the lifespan and has been shown to play a role in learning, memory and in mood regulation. In adulthood it is influenced by extrinsic environmental factors such as exercise and stress. Intrinsic factors that regulate hippocampal neurogenesis include the orphan nuclear receptor TLX (Nr2e1) which is primarily expressed in the neurogenic niches of the brain. While mechanisms regulating adult hippocampal neurogenesis have been widely studied, less is known on how hippocampal neurogenesis is affected during adolescence. The aim of this study was to investigate the influence of both TLX and isolation stress on exercise-induced increases in neurogenesis in running and sedentary conditions during adolescence. Single- (isolation stress) wild type and Nr2e1-/- mice or pair-housed wild type mice were housed in sedentary conditions or allowed free access to running wheels for 3 wk during adolescence. A redn. of neuronal survival was evident in mice lacking TLX, and exercise did not increase hippocampal neurogenesis in these Nr2e1-/- mice. This suggests that TLX is necessary for the pro-neurogenic effects of exercise during adolescence. Interestingly, although social isolation during adolescence did not affect hippocampal neurogenesis, it prevented an exercise-induced increase in neurogenesis in the ventral hippocampus. Together these data demonstrate the importance of intrinsic and extrinsic factors in promoting an exercise-induced increase in neurogenesis at this key point in life.
- 308O’Leary, J. D.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. Regulation of Behaviour by the Nuclear Receptor TLX. Genes, Brain Behav. 2018, 17 (3), e12357, DOI: 10.1111/gbb.12357
- 309Kumar, R. A.; McGhee, K. A.; Leach, S.; Bonaguro, R.; Maclean, A.; Aguirre-Hernandez, R.; Abrahams, B. S.; Coccaro, E. F.; Hodgins, S.; Turecki, G.; Condon, A.; Muir, W. J.; Brooks-Wilson, A. R.; Blackwood, D. H.; Simpson, E. M. Initial Association of NR2E1 with Bipolar Disorder and Identification of Candidate Mutations in Bipolar Disorder, Schizophrenia, and Aggression through Resequencing. Am. J. Med. Genet., Part B 2008, 147B (6), 880– 889, DOI: 10.1002/ajmg.b.30696[Crossref], [PubMed], [CAS], Google Scholar313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFOnu7rJ&md5=4492c71454d36d17a372109768f8aeeeInitial association of NR2E1 with bipolar disorder and identification of candidate mutations in bipolar disorder, schizophrenia, and aggression through resequencingKumar, Ravinesh A.; McGhee, Kevin A.; Leach, Stephen; Bonaguro, Russell; Maclean, Alan; Aguirre-Hernandez, Rosalia; Abrahams, Brett S.; Coccaro, Emil F.; Hodgins, Sheilagh; Turecki, Gustavo; Condon, Anne; Muir, Walter J.; Brooks-Wilson, Angela R.; Blackwood, Douglas H.; Simpson, Elizabeth M.American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics (2008), 147B (6), 880-889CODEN: AJMGC9; ISSN:1552-4841. (Wiley-Liss, Inc.)Nuclear receptor 2E1 gene (NR2E1) resides within a 6q21-22 locus for bipolar disorder and schizophrenia. Mice deleted for Nr2e1 show altered neurogenesis, cortical and limbic abnormalities, aggression, hyperexcitability, and cognitive impairment. NR2E1 is therefore a positional and functional candidate for involvement in mental illness. We performed assocn. analyses in 394 patients with bipolar disorder, 396 with schizophrenia, and 479 controls using six common markers and haplotypes. We also performed a comprehensive mutation screen of NR2E1, resequencing its entire coding region, complete 5' and 3' untranslated regions, consensus splice-sites, and evolutionarily conserved regions in 126 humans with bipolar disorder, schizophrenia, or aggressive disorders. NR2E1 was assocd. with bipolar disorder I and II [odds ratio (OR = 0.77, P = 0.013), bipolar disorder I (OR = 0.77, P = 0.015), bipolar disorder in females (OR = 0.72, P = 0.009), and with age at onset ≤25 years (OR = 0.67, P = 0.006)], all of which remained significant after correcting for multiple comparisons. We identified eight novel candidate mutations that were absent in 325 controls; four of these were predicted to alter known neural transcription factor binding sites. Analyses of NR2E1 mRNA in human brain revealed forebrain-specific transcription. The data presented support the hypothesis that genetic variation at NR2E1 may be assocd. with susceptibility to brain-behavior disorders.
- 310Wang, Y. Y.; Hsu, S. H.; Tsai, H. Y.; Cheng, M. C. Genetic Analysis of the NR2E1 Gene as a Candidate Gene of Schizophrenia. Psychiatry Res. 2020, 293, 113386, DOI: 10.1016/j.psychres.2020.113386[Crossref], [PubMed], [CAS], Google Scholar314https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1ejsrnF&md5=1e82a84d45a065258e03a4547d384900Genetic analysis of the NR2E1 gene as a candidate gene of schizophreniaWang, Yu-Yuan; Hsu, Shih-Hsin; Tsai, Hsin-Yao; Cheng, Min-ChihPsychiatry Research (2020), 293 (), 113386CODEN: PSRSDR; ISSN:0165-1781. (Elsevier Ltd.)NR2E1 is implicated in the regulation of neurogenesis and considered as a candidate gene for schizophrenia. We resequenced all the exons of NR2E1 in 547 patients with schizophrenia and 567 controls from Taiwan. We identified five common SNPs with no assocn. with patients with schizophrenia. Further haplotype-based assocn. anal. showed that two haplotypes within NR2E1 were correlated with the schizophrenia risk. Four rare mutations located at untranslated regions were identified in patients with schizophrenia but not in our control sample. The present study suggests that NR2E1 is likely to play a significant role in conferring susceptibility to schizophrenia.
- 311Liu, H. K.; Wang, Y.; Belz, T.; Bock, D.; Takacs, A.; Radlwimmer, B.; Barbus, S.; Reifenberger, G.; Lichter, P.; Schütz, G. The Nuclear Receptor Tailless Induces Long-Term Neural Stem Cell Expansion and Brain Tumor Initiation. Genes Dev. 2010, 24 (7), 683– 695, DOI: 10.1101/gad.560310[Crossref], [PubMed], [CAS], Google Scholar315https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltFWlsrc%253D&md5=21efa027164c31a2ca1f7c76df1c8436The nuclear receptor tailless induces long-term neural stem cell expansion and brain tumor initiationLiu, Hai-Kun; Wang, Ying; Belz, Thorsten; Bock, Dagmar; Takacs, Andrea; Radlwimmer, Bernhard; Barbus, Sebastian; Reifenberger, Guido; Lichter, Peter; Schuetz, GuentherGenes & Development (2010), 24 (7), 683-695CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)Malignant gliomas are the most common primary brain tumors, and are assocd. with frequent resistance to therapy as well as poor prognosis. Here we demonstrate that the nuclear receptor tailless (Tlx), which in the adult is expressed exclusively in astrocyte-like B cells of the subventricular zone, acts as a key regulator of neural stem cell (NSC) expansion and brain tumor initiation from NSCs. Overexpression of Tlx antagonizes age-dependent exhaustion of NSCs in mice and leads to migration of stem/progenitor cells from their natural niche. The increase of NSCs persists with age, and leads to efficient prodn. of newborn neurons in aged brain tissues. These cells initiate the development of glioma-like lesions and gliomas. Glioma development is accelerated upon loss of the tumor suppressor p53. Tlx-induced NSC expansion and gliomagenesis are assocd. with increased angiogenesis, which allows for the migration and maintenance of brain tumor stem cells in the perivascular niche. We also demonstrate that Tlx transcripts are overexpressed in human primary glioblastomas in which Tlx expression is restricted to a subpopulation of nestin-pos. perivascular tumor cells. Our study clearly demonstrates how NSCs contribute to brain tumorigenesis driven by a stem cell-specific transcription factor, thus providing novel insights into the histogenesis and mol. pathogenesis of primary brain tumors.
- 312Park, H.-J.; Kim, J.-K.; Jeon, H.-M.; Oh, S.-Y.; Kim, S.-H.; Park, M.-J.; Soeda, A.; Nam, D.-H.; Kim, H. The Neural Stem Cell Fate Determinant TLX Promotes Tumorigenesis and Genesis of Cells Resembling Glioma Stem Cells. Mol. Cells 2010, 30 (5), 403– 408, DOI: 10.1007/s10059-010-0122-z[Crossref], [PubMed], [CAS], Google Scholar316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVyhur7L&md5=fa4f8b28fd33d8e372d1364a2708d9b4The neural stem cell fate determinant TLX promotes tumorigenesis and genesis of cells resembling glioma stem cellsPark, Hyo-Jung; Kim, Jun-Kyum; Jeon, Hye-Min; Oh, Se-Yeong; Kim, Sung-Hak; Park, Myung-Jin; Soeda, Akio; Nam, Do-Hyun; Kim, HyunggeeMolecules and Cells (2010), 30 (5), 403-408CODEN: MOCEEK; ISSN:1016-8478. (Korean Society for Molecular and Cellular Biology)A growing body of evidence indicates that deregulation of stem cell fate determinants is a hallmark of many types of malignancies. The neural stem cell fate determinant TLX plays a pivotal role in neurogenesis in the adult brain by maintaining neural stem cells. Here, we report a tumorigenic role of TLX in brain tumor initiation and progression. Increased TLX expression was obsd. in a no. of glioma cells and glioma stem cells, and correlated with poor survival of patients with gliomas. Ectopic expression of TLX in the U87MG glioma cell line and Ink4a/Arf-deficient mouse astrocytes (Ink4a/Arf-/- astrocytes) induced cell proliferation with a concomitant increase in cyclin D expression, and accelerated foci formation in soft agar and tumor formation in in vivo transplantation assays. Furthermore, overexpression of TLX in Ink4a/Arf-/- astrocytes inhibited cell migration and invasion and promoted neurosphere formation and Nestin expression, which are hallmark characteristics of glioma stem cells, under stem cell culture conditions. Our results indicate that TLX is involved in glioma stem cell genesis and represents a potential therapeutic target for this type of malignancy.
- 313Louis, D. N.; Ohgaki, H.; Wiestler, O. D.; Cavenee, W. K.; Burger, P. C.; Jouvet, A.; Scheithauer, B. W.; Kleihues, P. The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathologica 2007, 114, 97– 109[Crossref], [PubMed], [CAS], Google Scholar317https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2svgvVCltA%253D%253D&md5=41874b633369fa8ba13d31f1d2efc114The 2007 WHO classification of tumours of the central nervous systemLouis David N; Ohgaki Hiroko; Wiestler Otmar D; Cavenee Webster K; Burger Peter C; Jouvet Anne; Scheithauer Bernd W; Kleihues PaulActa neuropathologica (2007), 114 (2), 97-109 ISSN:0001-6322.The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO 'Blue Book', the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide.
- 314Cui, Q.; Yang, S.; Ye, P.; Tian, E.; Sun, G.; Zhou, J.; Sun, G.; Liu, X.; Chen, C.; Murai, K.; Zhao, C.; Azizian, K. T.; Yang, L.; Warden, C.; Wu, X.; D’Apuzzo, M.; Brown, C.; Badie, B.; Peng, L.; Riggs, A. D.; Rossi, J. J.; Shi, Y. Downregulation of TLX Induces TET3 Expression and Inhibits Glioblastoma Stem Cell Self-Renewal and Tumorigenesis. Nat. Commun. 2016, 7, 10637, DOI: 10.1038/ncomms10637[Crossref], [PubMed], [CAS], Google Scholar318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVOks7Y%253D&md5=78353fc29bb03ee6cb4329dca2ef64ddDownregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesisCui, Qi; Yang, Su; Ye, Peng; Tian, E.; Sun, Guoqiang; Zhou, Jiehua; Sun, Guihua; Liu, Xiaoxuan; Chen, Chao; Murai, Kiyohito; Zhao, Chunnian; Azizian, Krist T.; Yang, Lu; Warden, Charles; Wu, Xiwei; D'Apuzzo, Massimo; Brown, Christine; Badie, Behnam; Peng, Ling; Riggs, Arthur D.; Rossi, John J.; Shi, YanhongNature Communications (2016), 7 (), 10637CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)Glioblastomas have been proposed to be maintained by highly tumorigenic glioblastoma stem cells (GSCs) that are resistant to current therapy. Therefore, targeting GSCs is crit. for developing effective therapies for glioblastoma. In this study, we identify the regulatory cascade of the nuclear receptor TLX and the DNA hydroxylase Ten eleven translocation 3 (TET3) as a target for human GSCs. We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice. Treatment of human GSC-grafted mice with viral vector-delivered TLX shRNA or nanovector-delivered TLX siRNA inhibits tumor development and prolongs survival. Moreover, we identify TET3 as a potent tumor suppressor downstream of TLX to regulate the growth and self-renewal in GSCs. This study identifies the TLX-TET3 axis as a potential therapeutic target for glioblastoma.
- 315Dueva, E.; Singh, K.; Kalyta, A.; LeBlanc, E.; Rennie, P. S.; Cherkasov, A. Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor. Molecules 2018, 23 (11), 2967, DOI: 10.3390/molecules23112967[Crossref], [CAS], Google Scholar319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmt1Gis78%253D&md5=e826cc00b8f2c6a06cc64b7d1aa126cbComputer-aided discovery of small molecule inhibitors of transcriptional activity of TLX (NR2E1) nuclear receptorDueva, Evgenia; Singh, Kriti; Kalyta, Anastasia; LeBlanc, Eric; Rennie, Paul S.; Cherkasov, ArtemMolecules (2018), 23 (11), 2967/1-2967/10CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Orphan nuclear receptor TLX (NR2E1) plays a crit. role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in prostate and breast cancer. Therefore, inhibitors of TLX transcriptional activity may have a significant impact on the treatment of several crit. malignancies. However, the TLX protein possesses a non-canonical ligand-binding domain (LBD), which lacks a ligand-binding pocket (conventionally targeted in case of nuclear receptors) that complicates the development of small mol. inhibitors of TLX. Herein, we utilized a rational structure-based design approach to identify small mols. targeting the Atro-box binding site of human TLX LBD. As a result of virtual screening of 7 million mol. structures, 97 compds. were identified and evaluated in the TLX-responsive luciferase reporter assay. Among those, three chems. demonstrated 40-50% inhibition of luciferase-detected transcriptional activity of the TLX orphan nuclear receptor at a dose of 35 μM. The identified compds. represent the first class of small mol. inhibitors of TLX transcriptional activity identified via methods of computer-aided drug discovery.
- 316Milbrandt, J. Nerve Growth Factor Induces a Gene Homologous to the Glucocorticoid Receptor Gene. Neuron 1988, 1 (3), 183– 188, DOI: 10.1016/0896-6273(88)90138-9[Crossref], [PubMed], [CAS], Google Scholar320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXmtVGgurw%253D&md5=51f5ce2172370c86806cd5dc1776be74Nerve growth factor induces a gene homologous to the glucocorticoid receptor geneMilbrandt, JeffreyNeuron (1988), 1 (3), 183-8CODEN: NERNET; ISSN:0896-6273.Nerve growth factor (NGF) is required for the development and survival of sympathetic and neural crest-derived sensory neurons. The mechanism of action of NGF has been extensively studied in the NGF-responsive rat pheochromocytoma cell line, PC12. When treated with NGF, PC12 cells initiate neurite outgrowth and differentiate into cells with a neuronal phenotype. This process is prevented by RNA synthesis inhibitors. NGFI-B Is a gene, identified by differential hybridization, that is rapidly, but transiently induced in PC12 cells by NGF. The nucleotide sequence of the NGFI-B gene was detd., and it encodes a 61-kd protein with strong homologies to members of the glucocorticoid receptor gene family. The 2 regions of homol. between NGFI-B and this family of ligand-dependent transcriptional activators are the region corresponding th the DNA-binding domain and the region comprising the ligand-binding domain near the C-terminus. NGFI-B, as a possible ligand-dependent transcriptional activator induced by NGF, may play a role in initiating NGF-induced differentiation.
- 317Wang, Z.; Benoit, G.; Liu, J.; Prasad, S.; Aarnisalo, P.; Liu, X.; Xu, H.; Walker, N. P. C.; Perlmann, T. Structure and Function of Nurr1 Identifies a Class of Ligand- Independent Nuclear Receptors. Nature 2003, 423 (6939), 555– 560, DOI: 10.1038/nature01645[Crossref], [PubMed], [CAS], Google Scholar321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktVygtb4%253D&md5=d19448447ffb618404ae84e4aa37c505Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptorsWang, Zhulun; Benoit, Gerard; Liu, Jinsong; Prasad, Srividya; Aarnisalo, Piia; Liu, Xiaohong; Xu, Haoda; Walker, Nigel P. C.; Perlmann, ThomasNature (London, United Kingdom) (2003), 423 (6939), 555-560CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Members of the nuclear receptor (NR) superfamily of transcription factors modulate gene transcription in response to small lipophilic mols. Transcriptional activity is regulated by ligands binding to the carboxy-terminal ligand-binding domains (LBDs) of cognate NRs. A subgroup of NRs referred to as 'orphan receptors' lack identified ligands, however, raising issues about the function of their LBDs. Here we report the crystal structure of the LBD of the orphan receptor Nurr1 at 2.2 Å resoln. The Nurr1 LBD adopts a canonical protein fold resembling that of agonist-bound, transcriptionally active LBDs in NRs, but the structure has two distinctive features. First, the Nurr1 LBD contains no cavity as a result of the tight packing of side chains from several bulky hydrophobic residues in the region normally occupied by ligands. Second, Nurr1 lacks a 'classical' binding site for coactivators. Despite these differences, the Nurr1 LBD can be regulated in mammalian cells. Notably, transcriptional activity is correlated with the Nurr1 LBD adopting a more stable conformation. Our findings highlight a unique structural class of NRs and define a model for ligand-independent NR function.
- 318Murphy, E. P.; Conneely, O. M. Neuroendocrine Regulation of the Hypothalamic Pituitary Adrenal Axis by the Nurr1/Nur77 Subfamily of Nuclear Receptors. Mol. Endocrinol. 1997, 11 (1), 39– 47, DOI: 10.1210/mend.11.1.9874[Crossref], [PubMed], [CAS], Google Scholar322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXhvFKitg%253D%253D&md5=79bd59c463059604b5934fadd9dc5a1aNeuroendocrine regulation of the hypothalamic pituitary adrenal axis by the nurr1/nur77 subfamily of nuclear receptorsMurphy, Evelyn P.; Conneely, Orla M.Molecular Endocrinology (1997), 11 (1), 39-47CODEN: MOENEN; ISSN:0888-8809. (Endocrine Society)The present study was designed to examine the role of nurr1/nur77 subfamily of nuclear receptor transcription factors in the regulation of the hypothalamic/pituitary/adrenal axis at the neuroendocrine level. The authors demonstrate that this nuclear receptor subfamily can regulate the expression of the CRF and POMC genes by interacting with a specific cis-acting sequence in their proximal promoter regions. To examine the physiol. significance of this response, the authors have focused on the POMC gene. The authors provide evidence that nurr1 and nur77 are rapidly induced by CRF in primary pituitary cells and that this induction is mimicked by forskolin in an anterior cell line. Further, the authors demonstrate that both nurr1- and forskolin-dependent induction of a POMC-chloramphenicol acetyltransferase reporter gene are inhibited by mutation of the nurr1-binding site within the POMC promoters and that this site alone can confer cAMP responsiveness to a heterologous promoter. Finally, the authors provide evidence that the nurr1/nur77 response sequences pivotal to both nurr1/nur77-dependent pos. regulation and glucocorticoid receptor-dependent neg. regulation of the POMC gene. These data strongly support the conclusion that the nurr1/nur77 subfamily plays an important coordinate neuroendocrine-regulatory role at all levels of the hypothalamic/pituitary/adrenal axis.
- 319Paulsen, R. E.; Granås, K.; Johnsen, H.; Rolseth, V.; Sterri, S. Three Related Brain Nuclear Receptors, NGFI-B, Nurr1, and NOR-1, as Transcriptional Activators. J. Mol. Neurosci. 1995, 6 (4), 249– 255, DOI: 10.1007/BF02736784[Crossref], [PubMed], [CAS], Google Scholar323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XivV2rtLY%253D&md5=d9a21c3adc12d98742ca4ca27993f1c6Three related brain nuclear receptors, NGFI-B, Nurr1, and NOR-1, as transcriptional activatorsPaulsen, Ragnhild E.; Granas, Kjersti; Johnsen, Helge; Rolseth, Veslemoy; Sterri, SigrunJournal of Molecular Neuroscience (1995), 6 (4), 249-255CODEN: JMNEES; ISSN:0895-8696. (Humana)Three related orphan nuclear receptors that are expressed in the brain, NGFI-B, Nurr1, and NOR-1, were studied to compare their function as transcriptional activators. NGFI-B was able to activate (in the absence of added hormone) in CV1 cells both an NGFI-B-responsive luciferase reporter gene (contg. eight copies of a response element for NGFI-B upstream of a basal prolactin promoter driving the luciferase gene, NBRE8-LUC), a similar thyroid hormone-receptor-responsive reporter gene (TRE3-LUC), and a reporter gene with an authentic promoter from a Xenopus vitellogenin gene contg. two binding sites for the estrogen receptor (vit-LUC). NGFI-B activated NBRE8-LUC and TRE3-LUC (but not the vit-LUC) with an amino-terminal activation domain. Nurr1 was less promiscuous as a transcriptional activator, activating the NBRE8-LUC better than NGFI-B, but less than NGFI-B at the other reporter genes. NOR-1 activated only the NBRE8-LUC reporter gene. These results indicate that closely related nuclear receptors may differentiate between response elements or promoters and that difficult activation mechanisms exist depending on the promoter. This may contribute to regulation of specificity of target gene expression in the brain.
- 320Maira, M.; Martens, C.; Philips, A.; Drouin, J. Heterodimerization between Members of the Nur Subfamily of Orphan Nuclear Receptors as a Novel Mechanism for Gene Activation. Mol. Cell. Biol. 1999, 19 (11), 7549– 7557, DOI: 10.1128/MCB.19.11.7549[Crossref], [PubMed], [CAS], Google Scholar324https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmvFekt7k%253D&md5=6216924bd742d76309b033c091d273fdHeterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activationMaira, Mario; Martens, Christine; Philips, Alexandre; Drouin, JacquesMolecular and Cellular Biology (1999), 19 (11), 7549-7557CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)The authors have recently shown that the orphan nuclear receptor Nur77 (NGFI-B) is most active in transcription when it is interacting with a cognate DNA sequence as a homodimer. Further, the authors have shown that the target for Nur77 dimers, the Nur response element (NurRE), is responsive to physiol. stimuli in both endocrine and lymphoid cells, whereas other DNA targets of Nur77 action are not. The Nur77 subfamily also includes two related receptors, Nur-related factor 1 (Nurr1) and neuron-derived orphan receptor 1 (NOR-1). Often, more than one member of this subfamily is induced in response to extracellular signals. The authors now show that Nur77 and Nurr1 form heterodimers in vitro in the presence or absence of NurRE, and the authors have documented interactions between these proteins in vivo by using a two-hybrid system in mammalian cells. These heterodimers synergistically enhance transcription from NurRE reporters in comparison to that seen with homodimers. The naturally occurring NurRE from the pro-opiomelanocortin gene preferentially binds and activates transcription in the presence of Nur77 homo- or heterodimers, while a consensus NurRE sequence does not show this preference. Taken together, the data indicate that members of the Nur77 subfamily are most potent as heterodimers and that different dimers exhibit target sequence preference. Thus, the authors propose that a combinatorial code relying on specific NurRE sequences might be responsible for the activation of subsets of target genes by one of the members of the Nur77 subfamily of transcription factors.
- 321Perlmann, T.; Jansson, L. A Novel Pathway for Vitamin A Signaling Mediated by RXR Heterodimerization with NGFI-B and NURR1. Genes Dev. 1995, 9 (7), 769– 782, DOI: 10.1101/gad.9.7.769[Crossref], [PubMed], [CAS], Google Scholar325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXltVaht7c%253D&md5=c9ea7577edf4a5b92721144a5ef1382fA novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1Perlmann, Thomas; Jansson, LottieGenes & Development (1995), 9 (7), 769-82CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)In addn. to its role as a 9-cis retinoic acid receptor, RXR has an important role in the regulation of multiple hormonal pathways through heterodimerization with nuclear receptors. Here, we show that two orphan receptors, NGFI-B and NURR1, which have been shown previously to interact with DNA as monomers, also can heterodimerize with RXR. These heterodimers bind selectively to a class of retinoic acid response elements composed of direct repeats spaced by 5 nucleotides. In this respect they are similar to heterodimers formed between RXR and the receptor for all-trans retinoic acid, RAR. However, whereas RXR is inhibited in the RXR-RAR heterodimer, NGFI-B/NURR1 promote efficient activation in response to RXR ligands and therefore shift RXR from a silent to an active heterodimerization partner. These data show that NGFI-B and NURR1 can increase the potential of RXR to modulate gene expression in a ligand-dependent manner by allowing a distinct class of direct repeats to serve as specific RXR response elements. Because expression of both NGFI-B and NURR1 is rapidly induced by various growth factors, these findings also suggest a novel mechanism for convergence between vitamin A or retinoid and growth factor signaling pathways.
- 322Xiao, Q.; Castillo, S. O.; Nikodem, V. M. Distribution of Messenger RNAs for the Orphan Nuclear Receptors NURR1 and NUR77 (NGFI-B) in Adult Rat Brain Using in Situ Hybridization. Neuroscience 1996, 75 (1), 221– 230, DOI: 10.1016/0306-4522(96)00159-5[Crossref], [PubMed], [CAS], Google Scholar326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmslGhu7c%253D&md5=4a9fc77c30696c5fafd790f34ace88d4Distribution of messenger RNAs for the orphan nuclear receptors Nurr1 and Nur77 (NGFI-B) in adult rat brain using in situ hybridizationXiao, Q.; Castillo, S. O.; Nikodem, V. M.Neuroscience (Oxford) (1996), 75 (1), 221-230CODEN: NRSCDN; ISSN:0306-4522. (Elsevier)Nurr1 and Nur77 (NGFI-B) are orphan nuclear receptors, belonging to the steroid/thyroid hormone receptor gene superfamily. They have conserved amino acid sequence in the zinc-finger DNA binding domains and similar COOH-terminal regions, but have no known ligands. However, different expression patterns during brain development and tissue distributions of these mRNAs imply that they might reflect a different transcriptional role in the brain. In this study, the regional and cellular expression of mRNAs encoding these two proteins in rat brain has been detd. by in situ hybridization. Nurr1 mRNA is highly expressed in the piriform and entorhinal cortices, hippocampus, medial habenular and paraventricular thalamic nuclei. Moderate labeling was detected in layers II-V of most of the cerebral cortex, and in the dorsal lateral geniculate nucleus, substantia nigra (pars compacta and reticularis) and interpeduncular nucleus. No Nurr1 hybridization signal was seen in the rhombencephalon. In the cerebellum, Nurr1 mRNA is present in the internal granular cell layer and Purkinje cell layer. In contrast, Nur77 has a widespread distribution, with the highest level of expression in the cerebral cortex. Moderate hybridization signals were detected in the hippocampus, the lateral dorsal and posterior nuclei, reuniens thalamic nuclei, and paraventricular and supraoptic hypothalamic nuclei. In the rhombencephalon, higher signals were present in the medial and lateral vestibular, dorsal cochlear and facial, and raphe magnus nuclei. Nur77 signal was also detected in the nucleus of the spinal tract of the trigeminal nerve. In the cerebellum, Nur77 mRNA is highly expressed in the Purkinje cell layer and lateral deep nucleus of the cerebellum. Our results show that Nurr1 and Nur77 mRNAs have both overlapping and different distribution patterns within the brain, suggesting that they might regulate different sets of responsive genes.
- 323Zetterström, R. H.; Williams, R.; Perlmann, T.; Olson, L. Cellular Expression of the Immediate Early Transcription Factors Nurr1 and NGFI-B Suggests a Gene Regulatory Role in Several Brain Regions Including the Nigrostriatal Dopamine System. Mol. Brain Res. 1996, 41 (1–2), 111– 120, DOI: 10.1016/0169-328X(96)00074-5[Crossref], [PubMed], [CAS], Google Scholar327https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s%252FjvVentQ%253D%253D&md5=ae85e40af8cba5f2a83e641a50571d21Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine systemZetterstrom R H; Williams R; Perlmann T; Olson LBrain research. Molecular brain research (1996), 41 (1-2), 111-20 ISSN:0169-328X.Nurr1 and NGFI-B are closely related orphan members of the steroid-thyroid hormone receptor family involved in immediate early responses to stimuli such as growth factors. In-situ hybridization in the developing and adult mouse and rat demonstrated Nurr1 mRNA in several regions during early central nervous system (CNS) development. Expression persisted through the pre- and postnatal periods and was also found in several areas in the adult CNS. Positive areas include the olfactory bulb, parts of the cortex, the hippocampal formation and substantia nigra where Nurr1 and tyrosine hydroxylase mRNAs were co-expressed. 6-Hydroxydopamine-induced degeneration of mesencephalic dopamine neurons led to a corresponding loss of Nurr1 mRNA, demonstrating a link between Nurr1 and dopaminergic neurons. NGFI-B mRNA was not found in the prenatal CNS but was highly expressed in the adult brain in many areas including the olfactory bulb, cortex, basal ganglia and hippocampus. The spatiotemporal distribution of Nurr1 and NGFI-B mRNAs suggests that these transcription factors are involved in the development and maturation of specific sets of CNS neurons. The experimental data imply that one of these functions may be to control gene regulatory events important for development and function of those neurons that degenerate in patients with Parkinson's disease.
- 324Chao, L. C.; Wroblewski, K.; Zhang, Z.; Pei, L.; Vergnes, L.; Ilkayeva, O. R.; Ding, S. Y.; Reue, K.; Watt, M. J.; Newgard, C. B.; Pilch, P. F.; Hevener, A. L.; Tontonoz, P. Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77. Diabetes 2009, 58 (12), 2788– 2796, DOI: 10.2337/db09-0763[Crossref], [PubMed], [CAS], Google Scholar328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFKlurfN&md5=5c4064106cef9dec4dececf60f992564Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77Chao, Lily C.; Wroblewski, Kevin; Zhang, Zidong; Pei, Liming; Vergnes, Laurent; Ilkayeva, Olga R.; Ding, Shi Ying; Reue, Karen; Watt, Matthew J.; Newgard, Christopher B.; Pilch, Paul F.; Hevener, Andrea L.; Tontonoz, PeterDiabetes (2009), 58 (12), 2788-2796CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)Nur77 is an orphan nuclear receptor with pleotropic functions. Previous studies have identified Nur77 as a transcriptional regulator of glucose utilization genes in skeletal muscle and gluconeogenesis in liver. However, the net functional impact of these pathways is unknown. To examine the consequence of Nur77 signaling for glucose metab. in vivo, we challenged Nur77 null mice with high-fat feeding. Wild-type and Nur77 null mice were fed a high-fat diet (60% calories from fat) for 3 mo. We detd. glucose tolerance, tissue-specific insulin sensitivity, oxygen consumption, muscle and liver lipid content, muscle insulin signaling, and expression of glucose and lipid metab. genes. Mice with genetic deletion of Nur77 exhibited increased susceptibility to diet-induced obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp studies revealed greater high-fat diet-induced insulin resistance in both skeletal muscle and liver of Nur77 null mice compared with controls. Loss of Nur77 expression in skeletal muscle impaired insulin signaling and markedly reduced GLUT4 protein expression. Muscles lacking Nur77 also exhibited increased triglyceride content and accumulation of multiple even-chained acylcarnitine species. In the liver, Nur77 deletion led to hepatic steatosis and enhanced expression of lipogenic genes, likely reflecting the lipogenic effect of hyperinsulinemia. Collectively, these data demonstrate that loss of Nur77 influences systemic glucose metab. and highlight the physiol. contribution of muscle Nur77 to this regulatory pathway.
- 325Zhan, Y.; Chen, Y.; Zhang, Q.; Zhuang, J.; Tian, M.; Chen, H.; Zhang, L.; Zhang, H.; He, J.; Wang, W.; Wu, R.; Wang, Y.; Shi, C.; Yang, K.; Li, A.; Xin, Y.; Li, T. Y.; Yang, J. Y.; Zheng, Z.; Yu, C.; Lin, S.-C.; Chang, C.; Huang, P.; Lin, T.; Wu, Q. The Orphan Nuclear Receptor Nur77 Regulates LKB1 Localization and Activates AMPK. Nat. Chem. Biol. 2012, 8 (11), 897– 904, DOI: 10.1038/nchembio.1069[Crossref], [PubMed], [CAS], Google Scholar329https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlCqu7jF&md5=f00c49daf55792014107d6857e8b729bThe orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPKZhan, Yan-yan; Chen, Yan; Zhang, Qian; Zhuang, Jia-jia; Tian, Min; Chen, Hang-zi; Zhang, Lian-ru; Zhang, Hong-kui; He, Jian-ping; Wang, Wei-jia; Wu, Rong; Wang, Yuan; Shi, Chunfang; Yang, Kai; Li, An-zhong; Xin, Yong-zhen; Li, Terytty Yang; Yang, James Y.; Zheng, Zhong-hui; Yu, Chun-dong; Lin, Sheng-Cai; Chang, Chawn-shang; Huang, Pei-qiang; Lin, Tianwei; Wu, QiaoNature Chemical Biology (2012), 8 (11), 897-904CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Liver kinase B1 (LKB1) has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). The regulation of LKB1 function, however, is still poorly understood. Here we demonstrate that the orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. This Nur77 function is antagonized by the chem. compd. Et 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), which interacts with Nur77 with high affinity and at specific sites. TMPA binding of Nur77 results in the release and shuttling of LKB1 to the cytoplasm to phosphorylate AMPKα. Moreover, TMPA effectively reduces blood glucose and alleviates insulin resistance in type II db/db and high-fat diet- and streptozotocin-induced diabetic mice but not in diabetic littermates with the Nur77 gene knocked out. This study attains a mechanistic understanding of the regulation of LKB1-AMPK axis and implicates Nur77 as a new and amenable target for the design and development of therapeutics to treat metabolic diseases.
- 326Kurakula, K.; Vos, M.; Logiantara, A.; Roelofs, J. J.; Nieuwenhuis, M. A.; Koppelman, G. H.; Postma, D. S.; van Rijt, L. S.; de Vries, C. J. M. Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-KB Activity in Lung Epithelial Cells. J. Immunol. 2015, 195 (4), 1388– 1398, DOI: 10.4049/jimmunol.1401714[Crossref], [PubMed], [CAS], Google Scholar330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht12gtrbF&md5=1925aa0e74194a59c7e9d56ae504570aNuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial CellsKurakula, Kondababu; Vos, Mariska; Logiantara, Adrian; Roelofs, Joris J.; Nieuwenhuis, Maartje A.; Koppelman, Gerard H.; Postma, Dirkje S.; van Rijt, Leonie S.; de Vries, Carlie J. M.Journal of Immunology (2015), 195 (4), 1388-1398CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)Allergic asthma is characterized by persistent chronic airway inflammation, which leads to mucus hypersecretion and airway hyperresponsiveness. Nuclear receptor Nur77 plays a pivotal role in distinct immune and inflammatory cells and is expressed in eosinophils and lung epithelium. However, the role of Nur77 in allergic airway inflammation has not been studied so far. In the present study, we detd. the role of Nur77 in airway inflammation using a murine model of OVA-induced allergic airway inflammation. We found that OVA-challenged Nur77 knockout (KO) mice show significantly enhanced infiltration of inflammatory cells, including eosinophils and lymphocytes, and aggravated mucus prodn. The infiltration of macrophages is limited in this model and was similar in wild-type and Nur77 KO mice. Higher levels of Th2 cytokines were found in bronchoalveolar lavage fluid and draining lymph node cells of Nur77-KO mice, as well as increased serum IgG1 and IgG2a levels. Knockdown of Nur77 in human lung epithelial cells resulted in a marked increase in IκBα phosphorylation, corresponding with elevated NF-κB activity, whereas Nur77 overexpression decreased NF-κB activity. Consistently, Nur77 significantly decreased mRNA levels of inflammatory cytokines and Muc5ac expression and also attenuated mucus prodn. in lung epithelial cells. To further corroborate these findings, we searched for assocn. of single nucleotide polymorphisms in Nur77 gene with asthma and with the severity of bronchial hyperresponsiveness. We identified three Nur77 single nucleotide polymorphisms showing assocn. with severity of bronchial hyperresponsiveness in asthma patients. Collectively, these findings support a protective role of Nur77 in OVA-induced airway inflammation and identify Nur77 as a novel therapeutic target for airway inflammation.
- 327Hamers, A. A.J.; Vos, M.; Rassam, F.; Marinkovic, G.; Kurakula, K.; van Gorp, P. J.; de Winther, M. P.J.; Gijbels, M. J.J.; de Waard, V.; de Vries, C. J.M. Bone Marrow-Specific Deficiency of Nuclear Receptor Nur77 Enhances Atherosclerosis. Circ. Res. 2012, 110 (3), 428– 438, DOI: 10.1161/CIRCRESAHA.111.260760[Crossref], [PubMed], [CAS], Google Scholar331https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVert7g%253D&md5=6a1e5a07fb7e20e16114e45977399821Bone Marrow-Specific Deficiency of Nuclear Receptor Nur77 Enhances AtherosclerosisHamers, Anouk A. J.; Vos, Mariska; Rassam, Fadi; Marinkovic, Goran; Kurakula, Kondababu; van Gorp, Patrick J.; de Winther, Menno P. J.; Gijbels, Marion J. J.; de Waard, Vivian; de Vries, Carlie J. M.Circulation Research (2012), 110 (3), 428-438CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Rationale: Nuclear receptor Nur77, also known as NR4A1, TR3, or NGFI-B, is expressed in human atherosclerotic lesions in macrophages, endothelial cells, T cells and smooth muscle cells. Macrophages play a crit. role in atherosclerosis and the function of Nur77 in lesion macrophages has not yet been investigated. Objective: This study aims to delineate the function of Nur77 in macrophages and to assess the effect of bone marrow-specific deficiency of Nur77 on atherosclerosis. Methods and results: We investigated Nur77 in macrophage polarization using bone marrow-derived macrophages (BMM) from wild-type and Nur77-knockout (Nur77) mice. Nur77 BMM exhibit changed expression of M2-specific markers and an inflammatory M1-phenotype with enhanced expression of interleukin-12, IFNγ, and SDF-1α and increased NO synthesis in (non)-stimulated Nur77 BMM cells. SDF-1α expression in nonstimulated Nur77 BMM is repressed by Nur77 and the chemoattractive activity of Nur77 BMM is abolished by SDF-1α inhibiting antibodies. Furthermore, Nur77 mice show enhanced thioglycollate-elicited migration of macrophages and B cells. The effect of bone marrow-specific deficiency of Nur77 on atherosclerosis was studied in low d. lipoprotein receptor-deficient (Ldlr) mice. Ldlr mice with a Nur77-deficient bone marrow transplant developed 2.1-fold larger atherosclerotic lesions than wild-type bone marrow-transplanted mice. These lesions contain more macrophages, T cells, smooth muscle cells and larger necrotic cores. SDF-1α expression is higher in lesions of Nur77-transplanted mice, which may explain the obsd. aggravation of lesion formation. Conclusions: In conclusion, in bone marrow-derived cells the nuclear receptor Nur77 has an anti-inflammatory function, represses SDF-1α expression and inhibits atherosclerosis.
- 328Hanna, R. N.; Shaked, I.; Hubbeling, H. G.; Punt, J. A.; Wu, R.; Herrley, E.; Zaugg, C.; Pei, H.; Geissmann, F.; Ley, K.; Hedrick, C. C. NR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases Atherosclerosis. Circ. Res. 2012, 110 (3), 416– 427, DOI: 10.1161/CIRCRESAHA.111.253377[Crossref], [PubMed], [CAS], Google Scholar332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVert7s%253D&md5=c686ef9d972070d869945ec15f3e5beeNR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases AtherosclerosisHanna, Richard N.; Shaked, Iftach; Hubbeling, Harper G.; Punt, Jennifer A.; Wu, Runpei; Herrley, Erica; Zaugg, Claudia; Pei, Hong; Geissmann, Frederic; Ley, Klaus; Hedrick, Catherine C.Circulation Research (2012), 110 (3), 416-427CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Rationale: NR4A1 (Nur77) is a nuclear receptor that is expressed in macrophages and within atherosclerotic lesions, yet its function in atherosclerosis is unknown. Objective: Nur77 regulates the development of monocytes, particularly patrolling Ly6C monocytes that may be involved in resoln. of inflammation. We sought to det. how absence of nuclear receptor subfamily 4, group A, member 1 (NR4A1) in hematopoietic cells affected atherosclerosis development. Methods and results: Nur77 chimeric mice on a Ldlr background showed a 3-fold increase in atherosclerosis development when fed a Western diet for 20 wk, despite having a drastic redn. in Ly6C patrolling monocytes. In a second model, mice deficient in both Nur77 and ApoE (ApoENur77) also showed increased atherosclerosis after 11 wk of Western diet. Atherosclerosis was assocd. with a significant change in macrophage polarization toward a proinflammatory phenotype, with high expression of tumor necrosis factor-α and nitric oxide and low expression of Arginase-I. Moreover, we found increased expression of toll-like receptor 4 mRNA and protein in Nur77 macrophages as well as increased phosphorylation of the p65 subunit of NFκB. Inhibition of NFκB activity blocked excess activation of Nur77 macrophages. Conclusions: We conclude that the absence of Nur77 in monocytes and macrophages results in enhanced toll-like receptor signaling and polarization of macrophages toward a proinflammatory M1 phenotype. Despite having fewer monocytes, Nur77 mice developed significant atherosclerosis when fed a Western diet. These studies indicate that Nur77 is a novel target for modulating the inflammatory phenotype of monocytes and macrophages and may be important for regulation of atherogenesis.
- 329De Silva, S.; Han, S.; Zhang, X.; Huston, D. P.; Winoto, A.; Zheng, B. Reduction of the Incidence and Severity of Collagen-Induced Arthritis by Constitutive Nur77 Expression in the T Cell Lineage. Arthritis Rheum. 2005, 52 (1), 333– 338, DOI: 10.1002/art.20736[Crossref], [PubMed], [CAS], Google Scholar333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1Kit7o%253D&md5=3185bbf074edd734633505b13561ea00Reduction of the incidence and severity of collagen-induced arthritis by constitutive Nur77 expression in the T cell lineagede Silva, Swanthri; Han, Shuhua; Zhang, Xuejun; Huston, David P.; Winoto, Astar; Zheng, BiaoArthritis & Rheumatism (2005), 52 (1), 333-338CODEN: ARHEAW; ISSN:0004-3591. (John Wiley & Sons, Inc.)Objective: To test the hypothesis that constitutive expression of Nur77 in the T cell lineage will suppress the development and pathogenesis of collagen-induced arthritis (CIA) and to understand the mechanisms by which Nur77 overexpression influences the arthritogenic response to type II collagen (CII). Methods: Nur77-transgenic end wild-type C57BL/6 mice were immunized with CII and were monitored for the development and severity of arthritis. Pathol. changes were examd. by histol. and radiog. The effects of Nur77 overexpression on immune responses were evaluated by cytokine prodn. in vitro and serum levels of CII-specific antibodies. Sensitivity of T cells to apoptosis induction was analyzed in vitro following stimulation with anti-CD3 monoclonal antibody or glucocorticoid. Results: The incidence and severity of CIA was significantly decreased in Nur77-transgenic mice compared with wild-type controls. Attenuation of the disease was assocd. with increased apoptosis induction in transgenic T cells and decreased prodn. of CII-specific IgG2a antibodies in transgenic mice. Overexpression of Nur77 in the T cell compartment did not affect Th1/Th2 cytokine prodn. or balance. Conclusion: Nur77 overexpression in the T cell lineage attenuates the development and progression of CIA, probably by promoting activation-induced T cell apoptosis and by inhibiting CII-specific antibody prodn.
- 330Li, L.; Liu, Y.; Chen, H.; Li, F.; Wu, J.; Zhang, H.; He, J.; Xing, Y.; Chen, Y.; Wang, W.; Tian, X.; Li, A.; Zhang, Q.; Huang, P.; Han, J.; Lin, T.; Wu, Q. Impeding the Interaction between Nur77 and P38 Reduces LPS-Induced Inflammation. Nat. Chem. Biol. 2015, 11 (5), 339– 346, DOI: 10.1038/nchembio.1788[Crossref], [PubMed], [CAS], Google Scholar334https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlsVOns74%253D&md5=648de4a3c58bba85279ae13a37a6c0a2Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammationLi, Li; Liu, Yuan; Chen, Hang-zi; Li, Feng-wei; Wu, Jian-feng; Zhang, Hong-kui; He, Jian-ping; Xing, Yong-zhen; Chen, Yan; Wang, Wei-jia; Tian, Xu-yang; Li, An-zhong; Zhang, Qian; Huang, Pei-qiang; Han, Jiahuai; Lin, Tianwei; Wu, QiaoNature Chemical Biology (2015), 11 (5), 339-346CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine prodn. Nur77 directly assocs. with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compd., n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate (PDNPA), screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study assocs. the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.
- 331Beard, J. A.; Tenga, A.; Chen, T. The Interplay of NR4A Receptors and the Oncogene-Tumor Suppressor Networks in Cancer. Cell. Signalling 2015, 27 (2), 257– 266, DOI: 10.1016/j.cellsig.2014.11.009[Crossref], [PubMed], [CAS], Google Scholar335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2gsrfP&md5=06396e4f736fb8990292219337bb150cThe interplay of NR4A receptors and the oncogene-tumor suppressor networks in cancerBeard, Jordan A.; Tenga, Alexa; Chen, TaoshengCellular Signalling (2015), 27 (2), 257-266CODEN: CESIEY; ISSN:0898-6568. (Elsevier)A review. Nuclear receptor (NR) subfamily 4 group A (NR4A) is a family of three highly homologous orphan nuclear receptors that have multiple physiol. and pathol. roles, including some in cancer. These NRs are reportedly dysregulated in multiple cancer types, with many studies demonstrating pro-oncogenic roles for NR4A1 (Nur77) and NR4A2 (Nurr1). Addnl., NR4A1 and NR4A3 (Nor-1) are described as tumor suppressors in leukemia. The dysregulation and functions of the NR4A members are due to many factors, including transcriptional regulation, protein-protein interactions, and post-translational modifications. These various levels of intracellular regulation result from the signaling cross-talk of the NR4A members with various signaling pathways, many of which are relevant to cancer and likely explain the family members' functions in oncogenesis and tumor suppression. In this review, we discuss the multiple functions of the NR4A receptors in cancer and summarize a growing body of scientific literature that describes the interconnectedness of the NR4A receptors with various oncogene and tumor suppressor pathways.
- 332Li, H.; Kolluri, S. K.; Gu, J.; Dawson, M. I.; Cao, X.; Hobbs, P. D.; Lin, B.; Chen, G.; Lu, J.; Lin, F.; Xie, Z.; Fontana, J. A.; Reed, J. C.; Zhang, X. Cytochrome c Release and Apoptosis Induced by Mitochondrial Targeting of Nuclear Orphan Receptor TR3. Science 2000, 289 (5482), 1159– 1164, DOI: 10.1126/science.289.5482.1159[Crossref], [PubMed], [CAS], Google Scholar336https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmt1Wju74%253D&md5=eff25fa9c3782edaf7f7a70f0d8d00d5Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3Li, Hui; Kolluri, Siva Kumar; Gu, Jian; Dawson, Marcia I.; Cao, Xihua; Hobbs, Peter D.; Lin, Bingzhen; Chen, Guo-Quen; Lu, Jiang-Song; Lin, Feng; Xie, Zhihua; Fontana, Joseph A.; Reed, John C.; Zhang, Xiao-KunScience (Washington, D. C.) (2000), 289 (5482), 1159-1164CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)TR3, an immediate-early response gene and an orphan member of the steroid-thyroid hormone-retinoid receptor superfamily of transcription factors, regulates apoptosis through an unknown mechanism. In response to apoptotic stimuli, TR3 translocates from the nucleus to mitochondria to induce cytochrome c release and apoptosis. Mitochondrial targeting of TR3, but not its DNA binding and transactivation, is essential for its proapoptotic effect. Our results reveal a mechanism by which a nuclear transcription factor translocates to mitochondria to initiate apoptosis.
- 333Cao, X.; Liu, W.; Lin, F.; Li, H.; Kolluri, S. K.; Lin, B.; Han, Y.; Dawson, M. I.; Zhang, X. Retinoid X Receptor Regulates Nur77/Thyroid Hormone Receptor 3-Dependent Apoptosis by Modulating Its Nuclear Export and Mitochondrial Targeting. Mol. Cell. Biol. 2004, 24 (22), 9705– 9725, DOI: 10.1128/MCB.24.22.9705-9725.2004[Crossref], [PubMed], [CAS], Google Scholar337https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpslOnt74%253D&md5=159df472771d127c65299229117878d3Retinoid X receptor regulates Nur77/thyroid hormone receptor 3-dependent apoptosis by modulating its nuclear export and mitochondrial targetingCao, Xihua; Liu, Wen; Lin, Feng; Li, Hui; Kolluri, Siva Kumar; Lin, Bingzhen; Han, Young-hoon; Dawson, Marcia I.; Zhang, Xiao-kunMolecular and Cellular Biology (2004), 24 (22), 9705-9725CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)Retinoid X receptor (RXR) plays a central role in the regulation of intracellular receptor signaling pathways by acting as a ubiquitous heterodimerization partner of many nuclear receptors, including the orphan receptor Nur77 (also known as thyroid hormone receptor 3 or NGFI-B), which translocates from the nucleus to mitochondria, where it interacts with Bcl-2 to induce apoptosis. Here, we report that RXRα is required for nuclear export and mitochondrial targeting of Nur77 through their unique heterodimerization that is mediated by dimerization interfaces located in their DNA-binding domain. The effects of RXRα are attributed to a putative nuclear export sequence (NES) present in its carboxyl-terminal region. RXRα ligands suppress NES activity by inducing RXRα homodimerization or altering RXRα/Nur77 heterodimerization. The RXRα NES is also silenced by RXRα heterodimerization with retinoic acid receptor or vitamin D receptor. Consistently, we were able to show that the mitochondrial targeting of the RXRα/Nur77 heterodimer and its induction of apoptosis are potently inhibited by RXR ligands. Together, our results reveal a novel nongenotropic function of RXRα and its involvement in the regulation of the Nur77-dependent apoptotic pathway.
- 334Gilbert, F.; Morissette, M.; St-Hilaire, M.; Paquet, B.; Rouillard, C.; Di Paolo, T.; Lévesque, D. Nur77 Gene Knockout Alters Dopamine Neuron Biochemical Activity and Dopamine Turnover. Biol. Psychiatry 2006, 60 (6), 538– 547, DOI: 10.1016/j.biopsych.2006.04.023[Crossref], [PubMed], [CAS], Google Scholar338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XpvFels7o%253D&md5=2245f46b35f73767ddbeef7532dccf24Nur77 gene knockout alters dopamine turnoverGilbert, Francois; Morissette, Marc; St-Hilaire, Michel; Paquet, Brigitte; Rouillard, Claude; Di Paolo, Therese; Levesque, DanielBiological Psychiatry (2006), 60 (6), 538-547CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Inc.)Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors closely assocd. with dopamine neurotransmission in the central nervous system. Nur77 expression is strongly modulated by antipsychotic and anti-parkinsonian drugs in dopaminoceptive brain areas. However, the role of Nur77 in dopamine neuron activity and turnover remains elusive. We compared various behavioral and biochem. parameters between Nur77 knockout -/- and wild-type +/+ mice in basal and haloperidol-challenged conditions. We report here that Nur77-deficient mice display enhanced spontaneous locomotor activity, greater sensitivity to a small dose of the dopamine D2 receptor agonist quinpirole acting mainly at autoreceptor sites, and higher levels of the dopamine metabolite DOPAC relative to wild-type mice. Dopamine turnover disturbances are also found after acute challenge with haloperidol, a dopamine D2 receptor antagonist. These alterations are assocd. with increased tyrosine hydroxylase expression and activity, and reduced catechol-O-methyltransferase expression. Taken together, these results are consistent with the involvement of Nur77 in dopamine neuron biochem. activity and dopamine turnover.
- 335Rouillard, C.; Baillargeon, J.; Paquet, B.; St-Hilaire, M.; Maheux, J.; Lévesque, C.; Darlix, N.; Majeur, S.; Lévesque, D. Genetic Disruption of the Nuclear Receptor Nur77 (Nr4a1) in Rat Reduces Dopamine Cell Loss and L-Dopa-Induced Dyskinesia in Experimental Parkinson’s Disease. Exp. Neurol. 2018, 304, 143– 153, DOI: 10.1016/j.expneurol.2018.03.008[Crossref], [PubMed], [CAS], Google Scholar339https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlslGqsr0%253D&md5=fb94f98547dcfa8522268881b7d64caaGenetic disruption of the nuclear receptor Nur77 (Nr4a1) in rat reduces dopamine cell loss and L-Dopa-induced dyskinesia in experimental Parkinson's diseaseRouillard, Claude; Baillargeon, Joanie; Paquet, Brigitte; St-Hilaire, Michel; Maheux, Jerome; Levesque, Catherine; Darlix, Noemie; Majeur, Simon; Levesque, DanielExperimental Neurology (2018), 304 (), 143-153CODEN: EXNEAC; ISSN:0014-4886. (Elsevier Inc.)Parkinson's disease (PD) is an idiopathic progressive neurodegenerative disorder characterized by the loss of midbrain dopamine neurons. Levodopa (L-dopa) is the main pharmacol. approach to relieve PD motor symptoms. However, chronic treatment with L-Dopa is inevitably assocd. with the generation of abnormal involuntary movements (L-Dopa-induced dyskinesia). We have previously shown that Nr4a1 (Nur77), a transcription factor of the nuclear receptor family, is closely assocd. with dopamine neurotransmission in the mature brain. However, the role of Nr4a1 in the etiol. of PD and its treatment remain elusive. We report here that the neurotoxin 6-hydroxydopamine in rat lead to a rapid up-regulation of Nr4a1 in the substantia nigra. Genetic disruption of Nr4a1 in rat reduced neurotoxin-induced dopamine cell loss and L-Dopa-induced dyskinesia, whereas virally-driven striatal overexpression of Nr4a1 enhanced or partially restored involuntary movements induced by chronic L-Dopa in wild type and Nr4a1-deficient rats, resp. Collectively, these results suggest that Nr4a1 is involved in dopamine cell loss and L-Dopa-induced dyskinesia in exptl. PD.
- 336Novak, G.; Gallo, A.; Zai, C. C.; Meltzer, H. Y.; Lieberman, J. A.; Potkin, S. G.; Voineskos, A. N.; Remington, G.; Kennedy, J. L.; Levesque, D.; Le Foll, B. Association of the Orphan Nuclear Receptor NR4A1 with Tardive Dyskinesia. Psychiatr. Genet. 2010, 20 (1), 39– 43, DOI: 10.1097/YPG.0b013e3283351221[Crossref], [PubMed], [CAS], Google Scholar340https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MfksFWqsw%253D%253D&md5=6e5f0d45e83d6687932ec5eac2b7948dAssociation of the orphan nuclear receptor NR4A1 with tardive dyskinesiaNovak Gabriela; Gallo Alexandra; Zai Clement C; Meltzer Herbert Y; Lieberman Jeffrey A; Potkin Steven G; Voineskos Aristotle N; Remington Gary; Kennedy James L; Levesque Daniel; Le Foll BernardPsychiatric genetics (2010), 20 (1), 39-43 ISSN:.Recent evidence has identified the NR4A1 (NUR77, NGFI-B) gene as a strong candidate for involvement in tardive dyskinesia (TD). We have investigated the association of six single nucleotide polymorphisms within the NR4A family of genes with TD in a sample of 171 patients with schizophrenia of Caucasian descent. The NR4A1 single nucleotide polymorphism (SNP) marker rs2603751 showed a nominal association with the risk of TD, as well as with the extent of TD based on the Abnormal Involuntary Movements Scale (AIMS) scores. The haplotype generated by the markers rs2603751 and rs2701124 also showed association with TD and, after adjustment for multiple testing, both the NR4A1 marker rs2603751 and the haplotype continued to show a trend toward association with TD. Although the results of this study are limited by a small sample size, it presents important pilot data and warrants further investigation of the involvement of NR4A1 variants in TD.
- 337St-Hilaire, M.; Bourhis, E.; Lévesque, D.; Rouillard, C. Impaired Behavioural and Molecular Adaptations to Dopamine Denervation and Repeated L-DOPA Treatment in Nur77-Knockout Mice. Eur. J. Neurosci. 2006, 24 (3), 795– 805, DOI: 10.1111/j.1460-9568.2006.04954.x[Crossref], [PubMed], [CAS], Google Scholar341https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28rgs1Ontg%253D%253D&md5=d8bc0c6c02ecf8417643e3d95b1c153bImpaired behavioural and molecular adaptations to dopamine denervation and repeated L-DOPA treatment in Nur77-knockout miceSt-Hilaire Michel; Bourhis Emmanuelle; Levesque Daniel; Rouillard ClaudeThe European journal of neuroscience (2006), 24 (3), 795-805 ISSN:0953-816X.We have previously shown that dopamine (DA) denervation and repeated L-DOPA treatment modulate the pattern of Nur77 mRNA expression in the striatum. However, the exact role of this nuclear receptor in L-DOPA-induced molecular and behavioural adaptations observed in animal models of Parkinson's disease is still unknown. In the present study, we investigated the effects of Nur77 gene deletion on the development of behavioural sensitization and on changes in the regulation of neuropeptides and DA D(3) receptor expression following DA denervation and repeated L-DOPA treatment in Nur77+/+ and Nur77-/- hemiparkinsonian mice. One week postsurgery, hemiparkinsonian mice were treated with L-DOPA (10 mg/kg) plus benserazide (3 mg/kg) once a day for 7 days. Despite similar extents of nigrostriatal denervation, L-DOPA-induced rotational response was exacerbated in Nur77-/- mice compared to Nur77+/+ ones. However, the rate of increase of the rotational behaviour after repeated L-DOPA injections was similar in the two mouse strains. Lesioning the nigrostriatal pathway increased enkephalin (ENK) and neurotensin (NT) mRNA levels in both mouse strains. However, the up-regulation of these neuropeptides was significantly reduced in Nur77-/- mice. There was no difference in the modulation of D3 receptor density and dynorphin (DYN) mRNA expression between the two mouse strains. The present results suggest that Nur77 is involved in setting the threshold level for L-DOPA-induced rotational behaviour, rather than controlling the development of behavioural sensitization. This specific behavioural change is associated with a selective regulation of neuropeptide expression specifically in the indirect striatal output pathway.
- 338Éthier, I.; Beaudry, G.; St-Hilaire, M.; Milbrandt, J.; Rouillard, C.; Lévesque, D. The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression. Neuropsychopharmacology 2004, 29 (2), 335– 346, DOI: 10.1038/sj.npp.1300318[Crossref], [PubMed], [CAS], Google Scholar342https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXksl2hsg%253D%253D&md5=1fdc8193085152f4c93f68c458f51006The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene ExpressionEthier, Isabelle; Beaudry, Genevieve; St-Hilaire, Michel; Milbrandt, Jeff; Rouillard, Claude; Levesque, DanielNeuropsychopharmacology (2004), 29 (2), 335-346CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)Despite extensive investigation, the cellular mechanisms responsible for neuroleptic actions remain elusive. The authors have previously shown that neuroleptics modulated the expression of some members of the ligand-activated transcription factors (nuclear receptors) including the nerve-growth factor inducible gene B (NGFI-B or Nur77) and retinoid X receptor (RXR) isoforms. Using genetic and pharmacol. approaches, the authors investigated the role of NGFI-B and retinoids in acute behavioral and biochem. responses to dopamine antagonists. NGFI-B knockout (KO) mice display a profound alteration of haloperidol-induced catalepsy and striatal neuropeptide gene expression. Haloperidol-induced increase of striatal enkephalin mRNA is totally abolished in NGFI-B KO mice whereas the increase of neurotensin mRNA expression is reduced by 50%. Interestingly, catalepsy induced by raclopride, a specific dopamine D2/D3 antagonist is completely abolished in NGFI-B-deficient mice whereas the cataleptic response to SCH 23390, a dopamine D1 agonist, is preserved. Accordingly, the effects of haloperidol on striatal c-fos, Nor-1, and dynorphin mRNA expression are also preserved in NGFI-B-deficient mice. The cataleptic response and the increase of enkephalin mRNA expression induced by haloperidol can also be suppressed by administration of retinoid ligands 9-cis retinoic acid and docosahexaenoic acid. In addn., the authors demonstrate that haloperidol enhances colocalization of NGFI-B and RXRγ1 isoform mRNAs, suggesting that both NGFI-B and a RXR isoform are highly coexpressed after haloperidol administration. The data demonstrate, for the first time, that NGFI-B and retinoids are actively involved in the mol. cascade induced by neuroleptic drugs.
- 339Mahmoudi, S.; Samadi, P.; Gilbert, F.; Ouattara, B.; Morissette, M.; Grégoire, L.; Rouillard, C.; Di Paolo, T.; Lévesque, D. Nur77 MRNA Levels and L-Dopa-Induced Dyskinesias in MPTP Monkeys Treated with Docosahexaenoic Acid. Neurobiol. Dis. 2009, 36 (1), 213– 222, DOI: 10.1016/j.nbd.2009.07.017[Crossref], [PubMed], [CAS], Google Scholar343https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFajtLvJ&md5=f5479f7d4c5660bf43525545402d7516Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acidMahmoudi, Souha; Samadi, Pershia; Gilbert, Francois; Ouattara, Bazoumana; Morissette, Marc; Gregoire, Laurent; Rouillard, Claude; Di Paolo, Therese; Levesque, DanielNeurobiology of Disease (2009), 36 (1), 213-222CODEN: NUDIEM; ISSN:0969-9961. (Elsevier B.V.)We have previously shown that docosahexaenoic acid (DHA) significantly reduced L-Dopa-induced dyskinesia (LID) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys. In the present study, we measured for the first time mRNA levels of Nur77, an orphan nuclear receptor that participates to adaptive and/or aberrant dopamine-related behaviors, and retinoid X receptor γ1 (RXRγ1), a putative brain receptor for DHA and transcriptional partner of Nur77, in MPTP monkeys treated with L-Dopa and DHA. The RXRγ1 mRNA is strongly expressed in monkey caudate nucleus and putamen, but no change in levels of RXRγ1 was obsd. following MPTP and L-Dopa treatments. On the other hand, denervation reduced Nur77 mRNA levels, whereas chronic L-Dopa treatment strongly induced Nur77 transcripts. These modulations are taking place in substance P pos. cells and are assocd. with both caudate-putamen matrix and striosome compartments. Interestingly, combination of L-Dopa with DHA further increases Nur77 mRNA levels in the anterior caudate-putamen, and mainly in striosomes. This is accompanied by a significant inverse correlation between Nur77 mRNA levels and dyskinetic scores. Taken together, our results show that Nur77 expression is modulated following dopamine denervation and chronic L-Dopa therapy in a non-human primate model of Parkinson's disease, and suggest that strong modulation of Nur77 expression might be linked to a reduced risk to develop LIDs.
- 340Mount, M. P.; Zhang, Y.; Amini, M.; Callaghan, S.; Kulczycki, J.; Mao, Z.; Slack, R. S.; Anisman, H.; Park, D. S. Perturbation of Transcription Factor Nur77 Expression Mediated by Myocyte Enhancer Factor 2D (MEF2D) Regulates Dopaminergic Neuron Loss in Response to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). J. Biol. Chem. 2013, 288 (20), 14362– 14371, DOI: 10.1074/jbc.M112.439216[Crossref], [PubMed], [CAS], Google Scholar344https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvVGktL4%253D&md5=ea76c928074c7162e7d80b1cce784caaPerturbation of transcription factor Nur77 expression mediated by myocyte enhancer factor 2D (MEF2D) regulates dopaminergic neuron Loss in response to 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)Mount, Matthew P.; Zhang, Yi; Amini, Mandana; Callaghan, Steve; Kulczycki, Jerzy; Mao, Zixu; Slack, Ruth S.; Anisman, Hymie; Park, David S.Journal of Biological Chemistry (2013), 288 (20), 14362-14371CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)We have earlier reported the crit. nature of calpain-CDK5-MEF2 signaling in governing dopaminergic neuronal loss in vivo. CDK5 mediates phosphorylation of the neuronal survival factor myocyte enhancer factor 2 (MEF2) leading to its inactivation and loss. However, the downstream factors that mediate MEF2-regulated survival are unknown. Presently, we define Nur77 as one such crit. downstream survival effector. Following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo, Nur77 expression in the nigrostriatal region is dramatically reduced. This loss is attenuated by expression of MEF2. Importantly, MEF2 constitutively binds to the Nur77 promoter in neurons under basal conditions. This binding is lost following 1-methyl-4-phenylpyridinium treatment. Nur77 deficiency results in significant sensitization to dopaminergic loss following 1-methyl-4-phenylpyridinium/MPTP treatment, in vitro and in vivo. Furthermore, Nur77-deficient MPTP-treated mice displayed significantly reduced levels of dopamine and 3,4-Dihydroxyphenylacetic acid in the striatum as well as elevated post synaptic FosB activity, indicative of increased nigrostriatal damage when compared with WT MPTP-treated controls. Importantly, this sensitization in Nur77-deficient mice was rescued with ectopic Nur77 expression in the nigrostriatal system. These results indicate that the inactivation of Nur77, induced by loss of MEF2 activity, plays a crit. role in nigrostriatal degeneration in vivo.
- 341Éthier, I.; Kagechika, H.; Shudo, K.; Rouillard, C.; Lévesque, D. Docosahexaenoic Acid Reduces Haloperidol-Induced Dyskinesias in Mice: Involvement of Nur77 and Retinoid Receptors. Biol. Psychiatry 2004, 56 (7), 522– 526, DOI: 10.1016/j.biopsych.2004.06.036[Crossref], [PubMed], [CAS], Google Scholar345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnvV2ms7o%253D&md5=48225c5fb6a582e72d3caf13c07c005aDocosahexaenoic acid reduces haloperidol-induced dyskinesias in mice: Involvement of Nur77 and retinoid receptorsEthier, Isabelle; Kagechika, Hiroyuki; Shudo, Koichi; Rouillard, Claude; Levesque, DanielBiological Psychiatry (2004), 56 (7), 522-526CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Inc.)Background: Treatment of schizophrenia's symptoms with typical antipsychotic drugs shows some efficacy, but the induction of extrapyramidal symptoms represents a serious handicap, which considerably limits their usefulness. Recent evidence suggests that Nur77 (nerve growth factor-induced B) and retinoids are involved in biochem. and behavioral effects of antipsychotic drugs assocd. with striatal functions. Methods: We evaluated the effect of retinoid ligands on oral dyskinesias (vacuous chewing movements) induced by haloperidol in wild-type and Nur77-deficient mice. Results: Nur77 gene ablation (knockout) or administration of a retinoid antagonist induced vacuous chewing movements and exacerbated those induced by haloperidol, whereas the retinoid agonist docosahexaenoic acid (an ω-3 polyunsatd. fatty acid) reduced them. Both the prodyskinetic effect of the retinoid antagonist and the antidyskinetic effect of docosahexaenoic acid are dependent on the presence of Nur77, since these drugs remained inactive in Nur77 knockout mice. Conclusion: These results suggest that nuclear receptors Nur77 and retinoid X receptor are involved in haloperidol-induced dyskinesias and that retinoid agonists may represent a new way to improve typical antipsychotic drug therapy.
- 342Wei, X.; Gao, H.; Zou, J.; Liu, X.; Chen, D.; Liao, J.; Xu, Y.; Ma, L.; Tang, B.; Zhang, Z.; Cai, X.; Jin, K.; Xia, Y.; Wang, Q. Contra-Directional Coupling of Nur77 and Nurr1 in Neurodegeneration: A Novel Mechanism for Memantine-Induced Anti-Inflammation and Anti-Mitochondrial Impairment. Mol. Neurobiol. 2016, 53 (9), 5876– 5892, DOI: 10.1007/s12035-015-9477-7[Crossref], [PubMed], [CAS], Google Scholar346https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslensL7N&md5=82fa00641dd9edb20a750296adc77691Contra-directional Coupling of Nur77 and Nurr1 in Neurodegeneration: A Novel Mechanism for Memantine-Induced Anti-inflammation and Anti-mitochondrial ImpairmentWei, Xiaobo; Gao, Huimin; Zou, Jing; Liu, Xu; Chen, Dan; Liao, Jinchi; Xu, Yunqi; Ma, Long; Tang, Beisha; Zhang, Zhuohua; Cai, Xiang; Jin, Kunling; Xia, Ying; Wang, QingMolecular Neurobiology (2016), 53 (9), 5876-5892CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Recent evidence suggests that nerve growth factor IB (Nur77) and nuclear receptor related1 (Nurr1) are differentially involved in dopaminergic neurodegeneration. Since memantine has shown clin. relevant efficacy in Parkinson's disease (PD) and displayed a potent protective effect on dopaminergic neurons in exptl. PD models, we asked if it exerts its neuroprotection by regulating Nur77 and Nurr1 signaling. We adopted a well-established in vitro PD model, 6-hydroxydopamine (OHDA)-lesioned PC12 cells, to test our hypothesis. Different concns. of memantine were incubated with 6-OHDA-lesioned PC12 cells, and Nur77/Nurr1 and their related signaling mols. were examd. by Western blot and immunocytochem. Nur77-deficient PC12 cells were used to verify the influences of Nur77 on neurodegeneration and memantine-mediated neuroprotection. We found that memantine reversed Nur77 upregulation and restored Nurr1 downregulation in 6-OHDA-lesioned PC12 cells. 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and induced co-localization of Cyt c/HSP60/Nur77 in the cytosol. Memantine strongly reduced the sub-cellular translocations of Nur77/Cyt c/HSP60 under 6-OHDA-induced oxidative condition. Knockdown of Nur77 enhanced the viability of PC12 cells exposed to 6-OHDA, while memantine-induced neuroprotection was much less in the cells with Nur77 knockdown than in those without it. We conclude that Nur77 plays a crucial role in modulating mitochondrial impairment and contributes to neurodegeneration under the exptl. PD condition. Memantine effectively suppresses such Nur77-mediated neurodegeneration and promotes survival signaling through post-translational modification of Nurr1. Nur77 and Nurr1 present a contra-directionally coupling interaction in memantine-mediated neuroprotection.
- 343Popichak, K. A.; Hammond, S. L.; Moreno, J. A.; Afzali, M. F.; Backos, D. S.; Slayden, R. D.; Safe, S.; Tjalkens, R. B. Compensatory Expression of NuR77 and NURR1 Regulates NF-KB–Dependent Inflammatory Signaling in Astrocytes. Mol. Pharmacol. 2018, 94 (4), 1174– 1186, DOI: 10.1124/mol.118.112631[Crossref], [PubMed], [CAS], Google Scholar347https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVGgt7nF&md5=07bcd618fd1eeabc599b889f137eb1bdCompensatory expression of Nur77 and Nurr1 regulates NF-KB-dependent inflammatory signaling in astrocytesPopichak, Katriana A.; Hammond, Sean L.; Moreno, Julie A.; Afzali, Maryam F.; Backos, Donald S.; Slayden, Richard D.; Safe, Stephen; Tjalkens, Ronald B.Molecular Pharmacology (2018), 94 (4), 1174-1186CODEN: MOPMA3; ISSN:1521-0111. (American Society for Pharmacology and Experimental Therapeutics)We postulated that a recently developed NR4A receptor ligand, 1,1bis (3'indolyl) 1(pmethoxyphenyl) methane (C-DIM5), would suppress NF-KB-dependent inflammatory gene expression in astrocytes after treatment with 1-methyl-4-Ph 1, 2, 3, 6-tetrahydropyridine (MPTP) and the inflammatory cytokines interferon gamma and tumor necrosis factor a. C-DIM5 increased expression of Nur77 mRNA and suppressed expression ofmultiple neuroinflammatory genes. C-DIM5 also inhibited the expression of NFKB-regulated inflammatory and apoptotic genes in quant. polymerase chain reaction array studies and effected p65 binding to unique genes in chromatin immunopptn. next-generation sequencing expts. but did not prevent p65 translocation to the nucleus, suggesting a nuclear-specific mechanism. C-DIM5 prevented nuclear export of Nur77 in astrocytes induced by MPTP treatment and simultaneously recruited Nurr1 to the nucleus, consistent with known transrepressive properties of this receptor. Combined RNAi knockdown of Nur77 and Nurr1 inhibited the anti-inflammatory activity of C-DIM5, demonstrating that C-DIM5 requires these receptors to inhibit NF-KB. Collectively, these data demonstrate that NR4A1/Nur77 and NR4A2/Nurr1 dynamically regulated inflammatory gene expression in glia by modulating the transcriptional activity of NF-KB.
- 344Liu, T.-Y.; Yang, X.-Y.; Zheng, L.-T.; Wang, G.-H.; Zhen, X.-C. Activation of Nur77 in Microglia Attenuates Proinflammatory Mediators Production and Protects Dopaminergic Neurons from Inflammation-Induced Cell Death. J. Neurochem. 2017, 140 (4), 589– 604, DOI: 10.1111/jnc.13907[Crossref], [PubMed], [CAS], Google Scholar348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFWlsbbE&md5=c8ea37e76cdb97d5984ea9ddd73de629Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation-induced cell deathLiu, Tian-Ya; Yang, Xiao-Ying; Zheng, Long-Tai; Wang, Guang-Hui; Zhen, Xue-ChuJournal of Neurochemistry (2017), 140 (4), 589-604CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)Microglia-mediated neuroinflammation plays a crit. role in the pathol. development of Parkinson's disease (PD). Orphan nuclear receptor Nur77 is abundant in neurons, while its role in microglia-mediated neuroinflammation remains unclear. The present data demonstrated that the expression of Nur77 in microglia was reduced accompanied by microglia activation in response to lipopolysaccharide (LPS) in vitro and in exptl. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model. Nur77 over-expression or application of Nur77 agonist cytosporone B suppressed the expression of proinflammatory genes, such as inducible nitric oxide NOS, cyclooxygenase-2, IL-1β, and tumor necrosis factor-α in the activated microglia, while silenced Nur77 exaggerated the inflammatory responses in microglia. Moreover, activation of Nur77 suppressed the LPS-induced NF-κB activation which was partly dependent on p38 MAPK activity, since inhibition of p38 MAPK by SB203580 abolished the LPS-activated NF-κB in microglia. On the other hand, inhibition of p38 MAPK attenuated LPS-induced Nur77 redn. Furthermore, in a microglia-conditioned cultured media system, Nur77 ameliorated the cytotoxicity to MN9D dopaminergic cells. Lastly, cytosporone B attenuated microglia activation and loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model. Taken together, these findings revealed the first evidence that Nur77 was an important modulator in microglia function that assocd. with microglia-mediated dopaminergic neurotoxicity, and thus modulation of Nur77 may represent a potential novel target for treatment for neurodegenerative disease.
- 345Yan, J.; Huang, J.; Wu, J.; Fan, H.; Liu, A.; Qiao, L.; Shen, M.; Lai, X. Nur77 Attenuates Inflammatory Responses and Oxidative Stress by Inhibiting Phosphorylated IκB-α in Parkinson’s Disease Cell Model. Aging 2020, 12 (9), 8107– 8119, DOI: 10.18632/aging.103128[Crossref], [PubMed], [CAS], Google Scholar349https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFagurzN&md5=11c7b47b77d171378382d3590bfb410eNur77 attenuates inflammatory responses and oxidative stress by inhibiting phosphorylated IκB-α in Parkinson's disease cell modelYan, Junqiang; Huang, Jiarui; Wu, Jiannan; Fan, Hua; Liu, Anran; Qiao, Liang; Shen, Mengmeng; Lai, XiaoyiAging (2020), 12 (9), 8107-8119CODEN: AGINCN; ISSN:1945-4589. (Impact Journals LLC)Neuroinflammation and oxidative stress play key roles in the pathol. development of Parkinson's disease (PD). Nerve growth factor-induced gene B (Nur77) is closely related to dopamine neurotransmission, and its pathogenesis is unclear. This study aims to investigate the role and mechanism of Nur77 in a cell model of Parkinson's disease. Silencing Nur77 with siRNA can aggravate intracellular LDH release, increase the expression of pro-inflammatory genes (such as tumor necrosis factor a, nuclear factor κB (p65), monocyte chemotactic protein 1, interleukin-6), and decrease cell survival, decrease expression of nuclear factor E2-related factor(Nrf2), heme oxygenase 1, NADPH quinineoxidoreductase-1. Cytosporone B (Nur77 agonist) has the opposite effect to Nur77 silencing. PDTC (NF-κB inhibitor / antioxidant) can also inhibit pro-inflammatory genes to a similar degree as Cytosporone B. Phosphorylated IκB-α can be inhibited by Cytosporone B, while silencing Nur77 can increase the protein expression level of phosphorylated IκB-α. After silencing IκB-α, both Cytosporone B and siNur77 did not affect pro-inflammatory genes and antioxidant stress. These findings reveal the first evidence that Nur77 exerts anti-inflammatory and antioxidant stress effects by inhibiting IκB-α phosphorylation expression in a Parkinson cell model. Nur77 may be a potential therapeutic target for Parkinson's disease.
- 346Liebmann, M.; Hucke, S.; Koch, K.; Eschborn, M.; Ghelman, J.; Chasan, A. I.; Glander, S.; Schädlich, M.; Kuhlencord, M.; Daber, N. M.; Eveslage, M.; Beyer, M.; Dietrich, M.; Albrecht, P.; Stoll, M.; Busch, K. B.; Wiendl, H.; Roth, J.; Kuhlmann, T.; Klotz, L. Nur77 Serves as a Molecular Brake of the Metabolic Switch during T Cell Activation to Restrict Autoimmunity. Proc. Natl. Acad. Sci. U. S. A. 2018, 115 (34), E8017– E8026, DOI: 10.1073/pnas.1721049115[Crossref], [PubMed], [CAS], Google Scholar350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVCitLbK&md5=305091a88d2683a65f1407cf575acfe3Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunityLiebmann, Marie; Hucke, Stephanie; Koch, Kathrin; Eschborn, Melanie; Ghelman, Julia; Chasan, Achmet I.; Glander, Shirin; SchAdlich, Martin; Kuhlencord, Meike; Daber, Niklas M.; Eveslage, Maria; Beyer, Marc; Dietrich, Michael; Albrecht, Philipp; Stoll, Monika; Busch, Karin B.; Wiendl, Heinz; Roth, Johannes; Kuhlmann, Tanja; Klotz, LuisaProceedings of the National Academy of Sciences of the United States of America (2018), 115 (34), E8017-E8026CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)T cells critically depend on reprogramming of metabolic signatures to meet the bioenergetic demands during activation and clonal expansion. Here we identify the transcription factor Nur77 as a cell-intrinsic modulator of T cell activation. Nur77-deficient T cells are highly proliferative, and lack of Nur77 is assocd. with enhanced T cell activation and increased susceptibility for T cell-mediated inflammatory diseases, such as CNS autoimmunity, allergic contact dermatitis and collagen-induced arthritis. Importantly, Nur77 serves as key regulator of energy metab. in T cells, restricting mitochondrial respiration and glycolysis and controlling switching between different energy pathways. Transcriptional network anal. revealed that Nur77 modulates the expression of metabolic genes, most likely in close interaction with other transcription factors, esp. estrogen-related receptor α. In summary, we identify Nur77 as a transcriptional regulator of T cell metab., which elevates the threshold for T cell activation and confers protection in different T cell-mediated inflammatory diseases.
- 347Rothe, T.; Ipseiz, N.; Faas, M.; Lang, S.; Perez-Branguli, F.; Metzger, D.; Ichinose, H.; Winner, B.; Schett, G.; Krönke, G. The Nuclear Receptor Nr4a1 Acts as a Microglia Rheostat and Serves as a Therapeutic Target in Autoimmune-Driven Central Nervous System Inflammation. J. Immunol. 2017, 198 (10), 3878– 3885, DOI: 10.4049/jimmunol.1600638[Crossref], [PubMed], [CAS], Google Scholar351https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXns1SktLY%253D&md5=ec349e37553ce84b464e3f4bd496d4f4The Nuclear Receptor Nr4a1 Acts as a Microglia Rheostat and Serves as a Therapeutic Target in Autoimmune-Driven Central Nervous System InflammationRothe, Tobias; Ipseiz, Natacha; Faas, Maria; Lang, Stefanie; Perez-Branguli, Francesc; Metzger, Daniel; Ichinose, Hiroshi; Winner, Beate; Schett, Georg; Kroenke, GerhardJournal of Immunology (2017), 198 (10), 3878-3885CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)Microglia cells fulfill key homeostatic functions and essentially contribute to host defense within the CNS. Altered activation of microglia, in turn, has been implicated in neuroinflammatory and neurodegenerative diseases. In this study, we identify the nuclear receptor (NR) Nr4a1 as key rheostat controlling the activation threshold and polarization of microglia. In steady-state microglia, ubiquitous neuronal-derived stress signals such as ATP induced expression of this NR, which contributed to the maintenance of a resting and noninflammatory microglia phenotype. Global and microglia-specific deletion of Nr4a1 triggered the spontaneous and overwhelming activation of microglia and resulted in increased cytokine and NO prodn. as well as in an accelerated and exacerbated form of exptl. autoimmune encephalomyelitis. Ligand-induced activation of Nr4a1 accordingly ameliorated the course of this disease. Our current data thus identify Nr4a1 as regulator of microglia activation and potentially new target for the treatment of inflammatory CNS diseases such as multiple sclerosis.
- 348Zhao, Y.; Liu, Y.; Zheng, D. Alpha 1-Antichymotrypsin/SerpinA3 Is a Novel Target of Orphan Nuclear Receptor Nur77. FEBS J. 2008, 275 (5), 1025– 1038, DOI: 10.1111/j.1742-4658.2008.06269.x[Crossref], [PubMed], [CAS], Google Scholar352https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXivFaqtbs%253D&md5=077966f45d92e1f3f376c9cc6919fc4dAlpha 1-antichymotrypsin/SerpinA3 is a novel target of orphan nuclear receptor Nur77Zhao, Yongjuan; Liu, Yanxin; Zheng, DexianFEBS Journal (2008), 275 (5), 1025-1038CODEN: FJEOAC; ISSN:1742-464X. (Blackwell Publishing Ltd.)Nur77 is one member of the nuclear receptor superfamily. As a transcription factor, Nur77 participates in a variety of biol. processes, including T cell development, inflammatory responses, steroid hormone synthesis, and hepatic glucose metab. It typically acts via binding to the Nur77 responsive element (NBRE) in the promoter regions of its target genes. In the present study, we identified a novel Nur77-regulated gene, α1-antichymotrypsin/SerpinA3, via an approach combining computational prediction and wet-lab. validations. First, we identified 483 candidate genes via a human genome-wide scan for NBREs in their proximal promoters. Three out of 14 function-assocd. genes were further identified to be trans-activated by Nur77 in luciferase reporter gene assays in HEK 293T cells. The transactivation assay proved that the NBRE (-182 to -175) in the SerpinA3 promoter region is a novel Nur77-dependent functional motif in HEK 293T and HepG2 cells. Electrophoretic mobility shift and chromatin immunopptn. assays demonstrated that Nur77 phys. assocs. with the SerpinA3 promoter region both in vitro and in vivo. Nur77 overexpression and RNA interference-mediated Nur77 gene knockdown anal. confirmed that SerpinA3 is indeed a novel Nur77-targeted gene. These data may throw light on the function of Nur77 in inflammatory responses and acute-phase reactions as well as the development of Alzheimer's disease.
- 349Wang, L.; Zheng, Y.; Gao, X.; Liu, Y.; You, X. Retinoid X Receptor Ligand Regulates RXRα/Nur77-Dependent Apoptosis via Modulating Its Nuclear Export and Mitochondrial Targeting. Int. J. Clin. Exp. Pathol. 2017, 10 (11), 10770– 10780[PubMed], [CAS], Google Scholar353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38%252FivFynsA%253D%253D&md5=a3714587a04eebc300604affa6a6426cRetinoid X receptor ligand regulates RXRα/Nur77-dependent apoptosis via modulating its nuclear export and mitochondrial targetingWang Li; Gao Xiaoxiao; Liu Yingchun; You Xiaoqing; Zheng YansongInternational journal of clinical and experimental pathology (2017), 10 (11), 10770-10780 ISSN:.Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder disease in elderly. It is characterized by the formation of amyloid plaques and nerve cells apoptosis in the brain. This study focuses on the association between nerve cells apoptosis and nuclear receptors within AD. Thus, we detected the changes of the expression and subcellular localization of RXRα/Nur77 and the apoptotic rate of neuroblastoma cells, SH-SY5Y cells and nerve cells in C57BL/6 mouse hippocampus in Alzheimer's disease pathologic condition, and investigated the effect of RXRα exporting inhibition caused by 9-cis-RA on the apoptosis of neurons. We demonstrated that Aβ peptide and H2O2 treatment could result in the translocation of RXRα and Nur77 from the nucleus to the mitochondria, and the ligand of RXR, 9-cis-RA, treatment can block the above phenomenon. More importantly, 9-cis-RA treatment could reduce the apoptotic rate of neurons caused by H2O2 or Aβ stimulation via enhancing the expression level of Bcl-2 protein. Therefore, our studies revealed a critical role of RXRα/Nur77 in 9-cis-RA-mediated anti-apoptosis in nerve cells and provided novel information for better management of AD.
- 350Zhan, Y.; Du, X.; Chen, H.; Liu, J.; Zhao, B.; Huang, D.; Li, G.; Xu, Q.; Zhang, M.; Weimer, B. C.; Chen, D.; Cheng, Z.; Zhang, L.; Li, Q.; Li, S.; Zheng, Z.; Song, S.; Huang, Y.; Ye, Z.; Su, W.; Lin, S.-C.; Shen, Y.; Wu, Q. Cytosporone B Is an Agonist for Nuclear Orphan Receptor Nur77. Nat. Chem. Biol. 2008, 4 (9), 548– 556, DOI: 10.1038/nchembio.106[Crossref], [PubMed], [CAS], Google Scholar354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpvFGrt7g%253D&md5=0514b5b3d32810b2de3b0218479e23f7Cytosporone B is an agonist for nuclear orphan receptor Nur77Zhan, Yanyan; Du, Xiping; Chen, Hangzi; Liu, Jingjing; Zhao, Bixing; Huang, Danhong; Li, Guideng; Xu, Qingyan; Zhang, Mingqing; Weimer, Bart C.; Chen, Dong; Cheng, Zhe; Zhang, Lianru; Li, Qinxi; Li, Shaowei; Zheng, Zhonghui; Song, Siyang; Huang, Yaojian; Ye, Zhiyun; Su, Wenjin; Lin, Sheng-Cai; Shen, Yuemao; Wu, QiaoNature Chemical Biology (2008), 4 (9), 548-556CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Nuclear orphan receptor Nur77 has important roles in many biol. processes. However, a physiol. ligand for Nur77 has not been identified. Here, we report that the octaketide cytosporone B (Csn-B) is a naturally occurring agonist for Nur77. Csn-B specifically binds to the ligand-binding domain of Nur77 and stimulates Nur77-dependent transactivational activity towards target genes including Nr4a1 (Nur77) itself, which contains multiple consensus response elements allowing pos. autoregulation in a Csn-B-dependent manner. Csn-B also elevates blood glucose levels in fasting C57 mice, an effect that is accompanied by induction of multiple genes involved in gluconeogenesis. These biol. effects were not obsd. in Nur77-null (Nr4a1-/-) mice, which indicates that Csn-B regulates gluconeogenesis through Nur77. Moreover, Csn-B induced apoptosis and retarded xenograft tumor growth by inducing Nur77 expression, translocating Nur77 to mitochondria to cause cytochrome c release. Thus, Csn-B may represent a promising therapeutic drug for cancers and hypoglycemia, and it may also be useful as a reagent to increase understanding of Nur77 biol. function.
- 351Munoz-Tello, P.; Lin, H.; Khan, P.; De Vera, I. M. S.; Kamenecka, T. M.; Kojetin, D. J. Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1. J. Med. Chem. 2020, 63 (24), 15639– 15654, DOI: 10.1021/acs.jmedchem.0c00894[ACS Full Text], [CAS], Google Scholar355https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFShsrzL&md5=6f76ae9c9cb563d7e4ed80989366acc4Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1Munoz-Tello, Paola; Lin, Hua; Khan, Pasha; de Vera, Ian Mitchelle S.; Kamenecka, Theodore M.; Kojetin, Douglas J.Journal of Medicinal Chemistry (2020), 63 (24), 15639-15654CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Nurr1/NR4A2 is an orphan nuclear receptor transcription factor implicated as a drug target for neurol. disorders including Alzheimer's and Parkinson's diseases. Previous studies identified small-mol. NR4A nuclear receptor modulators, but it remains unclear if these ligands affect transcription via direct binding to Nurr1. We assessed 12 ligands reported to affect NR4A activity for Nurr1-dependent and Nurr1-independent transcriptional effects and the ability to bind the Nurr1 ligand-binding domain (LBD). Protein NMR structural footprinting data show that amodiaquine, chloroquine, and cytosporone B bind the Nurr1 LBD; ligands that do not bind include C-DIM12, celastrol, camptothecin, IP7e, isoalantolactone, Et 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), and three high-throughput screening hit derivs. Importantly, ligands that modulate Nurr1 transcription also show Nurr1-independent effects on transcription in a cell type-specific manner, indicating that care should be taken when interpreting the functional response of these ligands in transcriptional assays. These findings should help focus medicinal chem. efforts that desire to optimize Nurr1-binding ligands.
- 352Liu, J.-J.; Zeng, H.-N.; Zhang, L.-R.; Zhan, Y.-Y.; Chen, Y.; Wang, Y.; Wang, J.; Xiang, S.-H.; Liu, W.-J.; Wang, W.-J.; Chen, H.-Z.; Shen, Y.-M.; Su, W.-J.; Huang, P.-Q.; Zhang, H.-K.; Wu, Q. A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In Vivo and In Vitro. Cancer Res. 2010, 70 (9), 3628– 3637, DOI: 10.1158/0008-5472.CAN-09-3160[Crossref], [PubMed], [CAS], Google Scholar356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltlens7w%253D&md5=ef78038604088d871c376495a9b978c7A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In vivo and In vitroLiu, Jing-jing; Zeng, Hui-ni; Zhang, Lian-ru; Zhan, Yan-yan; Chen, Yan; Wang, Yuan; Wang, Juan; Xiang, Shao-hua; Liu, Wen-jun; Wang, Wei-jia; Chen, Hang-zi; Shen, Yue-mao; Su, Wen-jin; Huang, Pei-qiang; Zhang, Hong-kui; Wu, QiaoCancer Research (2010), 70 (9), 3628-3637CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Nur77 is a steroid orphan receptor that plays a crit. role in regulating proliferation, differentiation, and apoptosis, including acting as a switch for Bcl-2 function. We previously reported that the octaketide cytosporone B (Csn-B) is a natural agonist for Nur77. In this study, we synthesized a series of Csn-B analogs and performed a structure-activity anal. that suggested criteria for the development of a unique pharmacophore to activate Nur77. The components of the pharmacophore necessary for binding Nur77 included the benzene ring, the phenolic hydroxyl group, and the acyl chain of the Csn-B scaffold, whereas the key feature for activating the biol. function of Nur77 was the ester group. Csn-B analogs that bound Nur77 tightly not only stimulated its transactivation activity but also initiated mitochondrial apoptosis by means of novel cross-talk between Nur77 and BRE, an antiapoptotic protein regulated at the transcriptional level. Notably, the deriv. n-amyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl]acetate exhibited greater antitumor activity in vivo than its parent compds., highlighting particular interest in this compd. Our findings describe a pathway for rational design of Csn-B-derived Nur77 agonists as a new class of potent and effective antitumor agents. Cancer Res; 70(9); 3628-37.
- 353Yang, P.-B.; Hou, P.-P.; Liu, F.-Y.; Hong, W.-B.; Chen, H.-Z.; Sun, X.-Y.; Li, P.; Zhang, Y.; Ju, C.-Y.; Luo, L.-J.; Wu, S.-F.; Zhou, J.-X.; Wang, Z.-J.; He, J.-P.; Li, L.; Zhao, T.-J.; Deng, X.; Lin, T.; Wu, Q. Blocking PPARγ Interaction Facilitates Nur77 Interdiction of Fatty Acid Uptake and Suppresses Breast Cancer Progression. Proc. Natl. Acad. Sci. U. S. A. 2020, 117 (44), 27412– 27422, DOI: 10.1073/pnas.2002997117[Crossref], [PubMed], [CAS], Google Scholar357https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1Ghu7vN&md5=50e8290033350110d998d4d65aebb89bBlocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progressionYang, Peng-bo; Hou, Pei-pei; Liu, Fu-yuan; Hong, Wen-bin; Chen, Hang-zi; Sun, Xiao-yu; Li, Peng; Zhang, Yi; Ju, Cui-yu; Luo, Li-juan; Wu, Sheng-fu; Zhou, Jia-xin; Wang, Zhi-jing; He, Jian-ping; Li, Li; Zhao, Tong-Jin; Deng, Xianming; Lin, Tianwei; Wu, QiaoProceedings of the National Academy of Sciences of the United States of America (2020), 117 (44), 27412-27422CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigenesis. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degrdn. of Nur77. Cocrystallog. and functional anal. revealed that Csn-B, a Nur77-targeting compd., promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77's inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.
- 354Wang, W.; Wang, Y.; Chen, H.; Xing, Y.; Li, F.; Zhang, Q.; Zhou, B.; Zhang, H.; Zhang, J.; Bian, X.; Li, L.; Liu, Y.; Zhao, B.; Chen, Y.; Wu, R.; Li, A.; Yao, L.; Chen, P.; Zhang, Y.; Tian, X.; Beermann, F.; Wu, M.; Han, J.; Huang, P.; Lin, T.; Wu, Q. Orphan Nuclear Receptor TR3 Acts in Autophagic Cell Death via Mitochondrial Signaling Pathway. Nat. Chem. Biol. 2014, 10 (2), 133– 140, DOI: 10.1038/nchembio.1406[Crossref], [PubMed], [CAS], Google Scholar358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvV2hsLrM&md5=cc674e5fe1c3126f82b5749a8588c24bOrphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathwayWang, Wei-jia; Wang, Yuan; Chen, Hang-zi; Xing, Yong-zhen; Li, Feng-wei; Zhang, Qian; Zhou, Bo; Zhang, Hong-kui; Zhang, Jie; Bian, Xue-li; Li, Li; Liu, Yuan; Zhao, Bi-xing; Chen, Yan; Wu, Rong; Li, An-zhong; Yao, Lu-ming; Chen, Ping; Zhang, Yi; Tian, Xu-yang; Beermann, Friedrich; Wu, Mian; Han, Jiahuai; Huang, Pei-qiang; Lin, Tianwei; Wu, QiaoNature Chemical Biology (2014), 10 (2), 133-140CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Autophagy is linked to cell death, yet the assocd. mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of mol. events leading to cellular demise is launched by a specific chem. compd., 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.
- 355Wang, W.; Wang, Y.; Hou, P.-P.; Li, F.-W.; Zhou, B.; Chen, H.-Z.; Bian, X.-L.; Cai, Q.-X.; Xing, Y.-Z.; He, J.-P.; Zhang, H.; Huang, P.-Q.; Lin, T.; Wu, Q. Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity. Chem. Biol. 2015, 22 (8), 1040– 1051, DOI: 10.1016/j.chembiol.2015.06.023[Crossref], [PubMed], [CAS], Google Scholar359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KmtbbK&md5=9f18c8c678d2620b437d9f3c4ab1696aInduction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 ActivityWang, Wei-jia; Wang, Yuan; Hou, Pei-pei; Li, Feng-wei; Zhou, Bo; Chen, Hang-zi; Bian, Xue-li; Cai, Qi-xu; Xing, Yong-zhen; He, Jian-ping; Zhang, Hongkui; Huang, Pei-qiang; Lin, Tianwei; Wu, QiaoChemistry & Biology (Oxford, United Kingdom) (2015), 22 (8), 1040-1051CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)Apoptotic resistance is becoming a significant obstacle for cancer therapy as the majority of treatment takes the route of apoptotic induction. It is of great importance to develop an alternative strategy to induce cancer cell death. We previously reported that autophagic cell death mediated by nuclear receptor TR3 and driven by a chem. agonist, 1-(3,4,5-trihydroxyphenyl)nonan-1-one (THPN), is highly effective in the therapy of melanoma but not any other cancer types. Here, we discovered that the insensitivity of cancer cells to THPN originated from a high cellular Akt2 activity. Akt2 phosphorylation interferes with TR3 export to cytoplasm and targeting to mitochondria, which lead to the autophagic induction. Therefore, the TR3-mediated autophagy could be effectively induced in the otherwise insensitive cells by downregulating Akt2 activity. Highly effective antineoplastic compds. are developed through optimizing the structure of THPN. This study implicates a general strategy for cancer therapy by the induction of autophagic cell death.
- 356Hu, M.; Luo, Q.; Alitongbieke, G.; Chong, S.; Xu, C.; Xie, L.; Chen, X.; Zhang, D.; Zhou, Y.; Wang, Z.; Ye, X.; Cai, L.; Zhang, F.; Chen, H.; Jiang, F.; Fang, H.; Yang, S.; Liu, J.; Diaz-Meco, M. T.; Su, Y.; Zhou, H.; Moscat, J.; Lin, X.; Zhang, X.-K. Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy. Mol. Cell 2017, 66 (1), 141– 153, DOI: 10.1016/j.molcel.2017.03.008[Crossref], [PubMed], [CAS], Google Scholar360https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvFWgs7s%253D&md5=a8efd7d1312b3252511ad4d8cd8db045Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and AutophagyHu, Mengjie; Luo, Qiang; Alitongbieke, Gulimiran; Chong, Shuyi; Xu, Chenting; Xie, Lei; Chen, Xiaohui; Zhang, Duo; Zhou, Yuqi; Wang, Zhaokai; Ye, Xiaohong; Cai, Lijun; Zhang, Fang; Chen, Huibin; Jiang, Fuquan; Fang, Hui; Yang, Shanjun; Liu, Jie; Diaz-Meco, Maria T.; Su, Ying; Zhou, Hu; Moscat, Jorge; Lin, Xiangzhi; Zhang, Xiao-kunMolecular Cell (2017), 66 (1), 141-153.e6CODEN: MOCEFL; ISSN:1097-2765. (Elsevier Inc.)Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-assocd. factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a crit. intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.
- 357Jung, Y.-S.; Lee, H.-S.; Cho, H.-R.; Kim, K.-J.; Kim, J.-H.; Safe, S.; Lee, S.-O. Dual Targeting of Nur77 and AMPKα by Isoalantolactone Inhibits Adipogenesis in Vitro and Decreases Body Fat Mass in Vivo. Int. J. Obes. 2019, 43 (5), 952– 962, DOI: 10.1038/s41366-018-0276-x[Crossref], [CAS], Google Scholar361https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFSms7fP&md5=7e9eab7cc05227ff49cf98e8cf957bc7Dual targeting of Nur77 and AMPKα by isoalantolactone inhibits adipogenesis in vitro and decreases body fat mass in vivoJung, Yeon-Seop; Lee, Hyo-Seon; Cho, Hye-Rin; Kim, Keuk-Jun; Kim, Joung-Hee; Safe, Stephen; Lee, Syng-OokInternational Journal of Obesity (2019), 43 (5), 952-962CODEN: IJOBDP; ISSN:0307-0565. (Nature Research)Background: Suppression of adipogenesis has been considered as a potential target for the prevention and treatment of obesity and assocd. metabolic disorders, and the nuclear receptor 4A1 (NR4A1/Nur77) and AMPKα are known to play important roles during early and intermediate stages of adipogenesis. Therefore, we hypothesized that dual targeting Nur77 and AMPKα would show strong inhibitory effect on adipogenesis. Methods: We screened a herbal medicine-based small mol. library to identify novel natural compds. dual targeting Nur77 and AMPKα, and the antiadipogenic effects and mechanisms of action of a "hit" compd. were studied in 3T3-L1 cells. In vivo antiobesity effects of the compd. were also investigated in high-fat diet (HFD)-induced obese mice. Results: We identified isoalantolactone (ISO) as a new NR4A1 inactivator that also activates AMPKα in 3T3-L1 cells. ISO, as expected, inhibited adipogenic differentiation of 3T3-L1 preadipocytes, accompanied by reduced mitotic clonal expansion (MCE) which occurs in the early stage of adipogenesis and decreased expression of genes required for MCE and cell cycle markers including cyclin A, cyclin D1. Furthermore, ISO reduced body wt. gain and fat mass (epididymal, s.c., perirenal, and inguinal white adipose tissues) in the high-fat diet-fed C57BL/6 N mice. Serum levels of triglycerides, aspartate transaminase, and alanine transaminase and hepatic steatosis were also significantly improved in the ISO-treated group compared to the high-fat diet control group. Conclusions: These results suggest that ISO dual targeting Nur77 and AMPKα during adipogenesis represents a novel class of mechanism-based antiadipogenic agents for treatment of obesity and assocd. metabolic disorders, including hyperlipidemia and fatty liver.
- 358Vinayavekhin, N.; Saghatelian, A. Discovery of a Protein-Metabolite Interaction between Unsaturated Fatty Acids and the Nuclear Receptor Nur77 Using a Metabolomics Approach. J. Am. Chem. Soc. 2011, 133 (43), 17168– 17171, DOI: 10.1021/ja208199h[ACS Full Text], [CAS], Google Scholar362https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1OnsbrJ&md5=4b50bc3a70cedccb6c188aa7959c0769Discovery of a Protein-Metabolite Interaction between Unsaturated Fatty Acids and the Nuclear Receptor Nur77 Using a Metabolomics ApproachVinayavekhin, Nawaporn; Saghatelian, AlanJournal of the American Chemical Society (2011), 133 (43), 17168-17171CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Neuron-derived clone 77 (Nur77) is an orphan nuclear receptor with currently no known natural ligands. Here we applied a metabolomics platform for detecting protein-metabolite interactions (PMIs) to identify lipids that bind to Nur77. Using this approach, we discovered that the Nur77 ligand-binding domain (Nur77LBD) enriches unsatd. fatty acids (UFAs) in tissue lipid mixts. The interaction of Nur77 with arachidonic acid and docosahexaenoic acid was subsequently characterized using a no. of biophys. and biochem. assays. Together these data indicate that UFAs bind to Nur77LBD to cause changes in the conformation and oligomerization of the receptor. UFAs are the only endogenous lipids reported to bind to Nur77, which highlights the use of metabolomics in the discovery of novel PMIs.
- 359Lakshmi, S. P.; Reddy, A. T.; Banno, A.; Reddy, R. C. Molecular, Chemical, and Structural Characterization of Prostaglandin A2 as a Novel Agonist for Nur77. Biochem. J. 2019, 476 (19), 2757– 2767, DOI: 10.1042/BCJ20190253[Crossref], [PubMed], [CAS], Google Scholar363https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlCks7rJ&md5=990368ac30502c102198dffa73c56c76Molecular, chemical, and structural characterization of prostaglandin A2 as a novel agonist for Nur77Lakshmi, Sowmya P.; Reddy, Aravind T.; Banno, Asoka; Reddy, Raju C.Biochemical Journal (2019), 476 (19), 2757-2767CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)Prior research that revealed a structurally atypical ligand-binding domain (LBD) and failed to locate an endogenous ligand had led to a classification of Nur77 as an orphan receptor. However, several more recent studies indicate that small synthetic mols. and unsatd. fatty acids can bind to Nur77. Discovery of addnl. endogenous ligands will facilitate our understanding of the receptor's functions and regulatory mechanisms. Our data have identified prostaglandin A2 (PGA2), a cyclopentenone prostaglandin (PG), as such a ligand. Cyclopentenone PGs exert their biol. effects primarily by forming protein adducts via the characteristic electrophilic beta-carbon(s) located in their cyclopentenone rings. Our data show that PGA2 induces Nur77 transcriptional activity by forming a covalent adduct between its endocyclic β-carbon, C9, and Cys566 in the receptor's LBD. The importance of this endocyclic β-carbon was substantiated by the failure of PGs without such electrophilic properties to react with Nur77. Calcd. chem. properties and data from reactive mol. dynamic simulations, intrinsic reaction coordinate modeling, and covalent mol. docking also corroborate the selectivity of PGA2's C9 β-carbon towards Nur77's Cys. In summary, our mol., chem., and structural characterization of the PGA2-Nur77 interaction provides the first evidence that PGA2 is an endogenous Nur77 agonist.
- 360Willems, S.; Kilu, W.; Ni, X.; Chaikuad, A.; Knapp, S.; Heering, J.; Merk, D. The Orphan Nuclear Receptor Nurr1 Is Responsive to Non-Steroidal Anti-Inflammatory Drugs. Commun. Chem. 2020, 3 (1), 85, DOI: 10.1038/s42004-020-0331-0[Crossref], [CAS], Google Scholar364https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVKksrvE&md5=780001615544ae3f93a28007f8f492beThe orphan nuclear receptor Nurr1 is responsive to non-steroidal anti-inflammatory drugsWillems, Sabine; Kilu, Whitney; Ni, Xiaomin; Chaikuad, Apirat; Knapp, Stefan; Heering, Jan; Merk, DanielCommunications Chemistry (2020), 3 (1), 85CODEN: CCOHCT; ISSN:2399-3669. (Nature Research)Nuclear receptor related 1 (Nurr1) is an orphan ligand-activated transcription factor and considered as neuroprotective transcriptional regulator with great potential as therapeutic target for neurodegenerative diseases. However, the collection of available Nurr1 modulators and mechanistic understanding of Nurr1 are limited. Here, we report the discovery of several structurally diverse non-steroidal anti-inflammatory drugs as inverse Nurr1 agonists demonstrating that Nurr1 activity can be regulated bidirectionally. As chem. tools, these ligands enable unraveling the co-regulatory network of Nurr1 and the mode of action distinguishing agonists from inverse agonists. In addn. to its ability to dimerize, we observe an ability of Nurr1 to recruit several canonical nuclear receptor co-regulators in a ligand-dependent fashion. Distinct dimerization states and co-regulator interaction patterns arise as discriminating factors of Nurr1 agonists and inverse agonists. Our results contribute a valuable collection of Nurr1 modulators and relevant mechanistic insights for future Nurr1 target validation and drug discovery.
- 361Ordentlich, P.; Yan, Y.; Zhou, S.; Heyman, R. A. Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1. J. Biol. Chem. 2003, 278 (27), 24791– 24799, DOI: 10.1074/jbc.M302167200[Crossref], [PubMed], [CAS], Google Scholar365https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltVSlsrY%253D&md5=14ff5059d95ea70552781473d260d340Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1Ordentlich, Peter; Yan, Yingzhuo; Zhou, Sihong; Heyman, Richard A.Journal of Biological Chemistry (2003), 278 (27), 24791-24799CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The purine anti-metabolite 6-mercaptopurine is one of the most widely used drugs for the treatment of acute childhood leukemia and chronic myelocytic leukemia. Developed in the 1950s, the drug is also being used as a treatment for inflammatory diseases such as Crohn's disease. The antiproliferative mechanism of action of this drug and other purine anti-metabolites has been demonstrated to be through inhibition of de novo purine synthesis and incorporation into nucleic acids. Despite the extensive clin. use and study of 6-mercaptopurine and other purine analogs, the cellular effects of these compds. remain relatively unknown. More recently, purine anti-metabolites have been shown to function as protein kinase inhibitors and to regulate gene expression. In an attempt to find small mol. regulators of the orphan nuclear receptor Nurr1, interestingly, we identified 6-mercaptopurine as a specific activator of this receptor. A detailed anal. of 6-mercaptopurine regulation of Nurr1 demonstrates that 6-mercaptopurine regulates Nurr1 through a region in the amino terminus. This activity can be inhibited by components of the purine biosynthesis pathway. These findings indicate that Nurr1 may play a role in mediating some of the antiproliferative effects of 6-mercaptopurine and potentially implicate Nurr1 as a mol. target for treatment of leukemias.
- 362Wansa, K. D. S. A.; Harris, J. M.; Yan, G.; Ordentlich, P.; Muscat, G. E. O. The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-Activation, Coactivator Recruitment, and Activation by the Purine Anti-Metabolite 6-Mercaptopurine. J. Biol. Chem. 2003, 278 (27), 24776– 24790, DOI: 10.1074/jbc.M300088200[Crossref], [PubMed], [CAS], Google Scholar366https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltVSlsrk%253D&md5=7e0a30de2f57a104fa8288fe90b485e9The AF-1 domain of the orphan nuclear receptor NOR-1 mediates trans-activation, coactivator recruitment, and activation by the purine anti-metabolite 6-mercaptopurineWansa, K. D. Senali Abayratna; Harris, Jonathan M.; Yan, Grace; Ordentlich, Peter; Muscat, George E. O.Journal of Biological Chemistry (2003), 278 (27), 24776-24790CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)NOR-1/NR4A3 is an "orphan member" of the nuclear hormone receptor superfamily. NOR-1 and its close relatives Nurr1 and Nur77 are members of the NR4A subgroup of nuclear receptors. Members of the NR4A subgroup are induced through multiple signal transduction pathways. They have been implicated in cell proliferation, differentiation, T-cell apoptosis, chondrosarcomas, neurol. disorders, inflammation, and atherogenesis. However, the mechanism of transcriptional activation, coactivator recruitment, and agonist-mediated activation remain obscure. Hence, we examd. the mol. basis of NOR-1-mediated activation. We obsd. that NOR-1 trans-activates gene expression in a cell- and target-specific manner; moreover, it operates in an activation function (AF)-1-dependent manner. The N-terminal AF-1 domain delimited to between amino acids 1 and 112, preferentially recruits the steroid receptor coactivator (SRC). Furthermore, SRC-2 modulates the activity of the AF-1 domain but not the C-terminal ligand binding domain (LBD). Homol. modeling indicated that the NOR-1 LBD was substantially different from that of hRORβ, a closely related AF-2-dependent receptor. In particular, the hydrophobic cleft characteristic of nuclear receptors was replaced with a very hydrophilic surface with a distinct topol. This observation may account for the inability of this nuclear receptor LBD to efficiently mediate cofactor recruitment and transcriptional activation. In contrast, the N-terminal AF-1 is necessary for cofactor recruitment and can independently conscript coactivators. Finally, we demonstrate that the purine anti-metabolite 6-mercaptopurine, a widely used antineoplastic and anti-inflammatory drug, activates NOR-1 in an AF-1-dependent manner. Addnl. 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity. We hypothesize that the NR4A subgroup mediates the genotoxic stress response and suggest that this subgroup may function as sensors that respond to genotoxicity.
- 363Yoo, Y. G.; Na, T. Y.; Yang, W. K.; Kim, H. J.; Lee, I. K.; Kong, G.; Chung, J. H.; Lee, M. O. 6-Mercaptopurine, an Activator of Nur77, Enhances Transcriptional Activity of HIF-1α Resulting in New Vessel Formation. Oncogene 2007, 26 (26), 3823– 3834, DOI: 10.1038/sj.onc.1210149[Crossref], [PubMed], [CAS], Google Scholar367https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlvFalu7Y%253D&md5=6dfa5569b47590e0086881347532c0106-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formationYoo, Y.-G.; Na, T.-Y.; Yang, W.-K.; Kim, H.-J.; Lee, I.-K.; Kong, G.; Chung, J.-H.; Lee, M.-O.Oncogene (2007), 26 (26), 3823-3834CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)Hypoxia-inducible factor-1α (HIF-1α) plays a central role in oxygen homeostasis. Previously, we reported that the orphan nuclear receptor Nur77 functions in stabilizing HIF-1α. Here, we demonstrate that 6-mercaptopurine (6-MP), an activator of the NR4A family members, enhances transcriptional activity of HIF-1. 6-MP enhanced the protein-level of HIF-1α as well as vascular endothelial growth factor (VEGF) in a dose- and time-dependent manner. The induction of HIF-1α was abolished by the transfection of either a dominant-neg. Nur77 mutant or si-Nur77, indicating a crit. role of Nur77 in the 6-MP action. The HIF-1α protein level remained up to 60 min in the presence of 6-MP when de novo protein synthesis was blocked by cycloheximide, suggesting that 6-MP induces stabilization of the HIF-1α protein. The fact that 6-MP decreased the assocn. of HIF-1α with von Hippel-Lindau protein and the acetylation of HIF-1α, may explain how 6-MP induced stability of HIF-1α. Further, 6-MP induced the transactivation function of HIF-1α by recruiting co-activator cyclic-AMP-response-element-binding protein. Finally, 6-MP enhanced the expression of HIF-1α and VEGF, and the formation of capillary tubes in human umbilical vascular endothelial cells. Together, our results provide a new insight for 6-MP action in the stabilization of HIF-1α and imply a potential application of 6-MP in hypoxia-assocd. human vascular diseases.
- 364Lee, H.-S.; Safe, S.; Lee, S.-O. Inactivation of the Orphan Nuclear Receptor NR4A1 Contributes to Apoptosis Induction by Fangchinoline in Pancreatic Cancer Cells. Toxicol. Appl. Pharmacol. 2017, 332, 32– 39, DOI: 10.1016/j.taap.2017.07.017[Crossref], [PubMed], [CAS], Google Scholar368https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1GitrvJ&md5=8362b6f90ea3e07cd74b9e092c142b9aInactivation of the orphan nuclear receptor nr4a1 contributes to apoptosis induction by fangchinoline in pancreatic cancer cellsLee, Hyo-Seon; Safe, Stephen; Lee, Syng-OokToxicology and Applied Pharmacology (2017), 332 (), 32-39CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)Previous studies have demonstrated that the orphan nuclear receptor NR4A1 is overexpressed in human pancreatic cancer and antagonizing this receptor promotes apoptosis and inhibits pancreatic cancer cells and tumor growth. In the present study, we identified fangchinoline, a bisbenzyltetrahydroisoquinoline alkaloid from Stephania tetrandra, as a new inactivator of nuclear NR4A1 and demonstrated that fangchinoline inhibits cell proliferation and induces apoptosis, in part, via the NR4A1-dependent pro-apoptotic pathways in human pancreatic cancer cells. It decreased expression of the antiapoptotic protein survivin by inhibiting Sp1-mediated transcription and induced oxidative stress-mediated endoplasmic reticulum (ER) stress in pancreatic cancer cells. These results suggest that inhibition of NR4A1-mediated transcriptional activity was involved in the anticancer effects of fangchinoline, and fangchinoline represents a novel class of mechanism-based anticancer agents targeting NR4A1 that is overexpressed in pancreatic cancer.
- 365Lee, S.-O.; Li, X.; Hedrick, E.; Jin, U.-H.; Tjalkens, R. B.; Backos, D. S.; Li, L.; Zhang, Y.; Wu, Q.; Safe, S. Diindolylmethane Analogs Bind NR4A1 and Are NR4A1 Antagonists in Colon Cancer Cells. Mol. Endocrinol. 2014, 28 (10), 1729– 1739, DOI: 10.1210/me.2014-1102[Crossref], [PubMed], [CAS], Google Scholar369https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslCns73K&md5=71c23c6b36e3b950d92f88c2d8d71068Diindolylmethane Analogs Bind Nr4a1 and Are Nr4a1 Antagonists In Colon Cancer CellsLee, Syng-Ook; Li, Xi; Hedrick, Erik; Jin, Un-Ho; Tjalkens, Ronald B.; Backos, Donald S.; Li, Li; Zhang, Yi; Wu, Qiao; Safe, StephenMolecular Endocrinology (2014), 28 (10), 1729-1739, 11 pp.CODEN: MOENEN; ISSN:1944-9917. (Endocrine Society)1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compds. exhibit antineoplastic activity in multiple cancer cell lines and the p-hydroxyphenyl analog (DIM-C-pPhOH) inactivates nuclear receptor 4A1 (NR4A1) in lung and pancreatic cancer cell lines. Using a series of 14 different p-substituted Ph C-DIMs, we show that several compds. including DIM-C-pPhOH directly interacted with the ligand binding domain of NR4A1. Computational-based mol. modeling studies showed high-affinity interactions of DIM-C-pPhOH and related compds. within the ligand binding pocket of NR4A1, and these same compds. decreased NR4A1-dependent transactivation in colon cancer cells transfected with a construct contg. 3 tandem Nur77 binding response elements linked to a luciferase reporter gene. Moreover, we also show that knockdown of NR4A1 by RNA interference (small interfering NR4A1) or treatment with DIM-C-pPhOH and related compds. decreased colon cancer cell growth, induced apoptosis, decreased expression of survivin and other Sp-regulated genes, and inhibited mammalian target of rapamycin signaling. Thus, C-DIMs such as DIM-C-pPhOH directly bind NR4A1 and are NR4A1 antagonists in colon cancer cells, and their antineoplastic activity is due, in part, to their interactions with nuclear NR4A1.
- 366Lee, S. O.; Abdelrahim, M.; Yoon, K.; Chintharlapalli, S.; Papineni, S.; Kim, K.; Wang, H.; Safe, S. Inactivation of the Orphan Nuclear Receptor TR3/Nur77 Inhibits Pancreatic Cancer Cell and Tumor Growth. Cancer Res. 2010, 70 (17), 6824– 6836, DOI: 10.1158/0008-5472.CAN-10-1992[Crossref], [PubMed], [CAS], Google Scholar370https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtV2rsLbF&md5=d32243cf686d3ac9ac80876ba3ac6a0cInactivation of the Orphan Nuclear Receptor TR3/Nur77 Inhibits Pancreatic Cancer Cell and Tumor GrowthLee, Syng-Ook; Abdelrahim, Maen; Yoon, Kyungsil; Chintharlapalli, Sudhakar; Papineni, Sabitha; Kim, Kyounghyun; Wang, Huamin; Safe, StephenCancer Research (2010), 70 (17), 6824-6836CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Activation of the orphan nuclear receptor TR3/Nur77 (NR4A1) promotes apoptosis and inhibits pancreatic tumor growth, but its endogenous function and the effects of its inactivation have yet to be detd. TR3 was overexpressed in human pancreatic tumors compared with nontumor tissue. Small interfering RNA-mediated knockdown of TR3 or cell treatment with the TR3 antagonist 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) decreased proliferation, induced apoptosis, and decreased expression of antiapoptotic genes including Bcl-2 and survivin in pancreatic cancer cells. Survivin suppression was mediated by formation of a TR3-Sp1-p300 DNA binding complex on the proximal GC-rich region of the survivin promoter. When administered in vivo, DIM-C-pPhOH induced apoptosis and inhibited tumor growth in an orthotopic model of pancreatic cancer, assocd. with inhibition of the same antiapoptotic markers obsd. in vitro. Our results offer preclin. validation of TR3 as a drug target for pancreatic cancer chemotherapy, based on the ability of TR3 inhibitors to block the growth of pancreatic tumors.
- 367Yoon, K.; Lee, S.-O.; Cho, S.-D.; Kim, K.; Khan, S.; Safe, S. Activation of Nuclear TR3 (NR4A1) by a Diindolylmethane Analog Induces Apoptosis and Proapoptotic Genes in Pancreatic Cancer Cells and Tumors. Carcinogenesis 2011, 32 (6), 836– 842, DOI: 10.1093/carcin/bgr040[Crossref], [PubMed], [CAS], Google Scholar371https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntFCksro%253D&md5=b93d269385bfc898334f2056cbcf46fdActivation of nuclear TR3 (NR4A1) by a diindolylmethane analog induces apoptosis and proapoptotic genes in pancreatic cancer cells and tumorsYoon, Kyung-Sil; Lee, Syng-Ook; Cho, Sung-Dae; Kim, Kyoung-Hyun; Khan, Sha-Heen; Safe, StephenCarcinogenesis (2011), 32 (6), 836-842CODEN: CRNGDP; ISSN:0143-3334. (Oxford University Press)NR4A1 (Nur77, TR3) is overexpressed in pancreatic tumors and activation of TR3 by 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (DIM-C-pPhOCH3) inhibits cell and tumor growth and induces apoptosis. Microarray anal. demonstrates that in L3.6pL pancreatic cancer cells DIM-C-pPhOCH3 induces genes assocd. with metab., homeostasis, signal transduction, transcription, stress, transport, immune responses, growth inhibition and apoptosis. Among the most highly induced growth inhibitory and proapoptotic genes including activating transcription factor 3 (ATF3), p21, cystathionase, dual specificity phosphatase 1 and growth differentiation factor 15, RNA interference studies demonstrated that induction of all but the later gene by DIM-C-pPhOCH3 were TR3-dependent. We also obsd. that DIM-C-pPhOCH3 induced Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and induction of TRAIL was ATF3 dependent. Results of this and previous studies demonstrate that TR3 is unique among nuclear receptors since nuclear TR3 is activated or deactivated by diindolylmethane derivs. to induce different apoptotic and growth inhibitory pathways that inhibit pancreatic cancer cell and tumor growth.
- 368Liu, J.; Wang, G.-H.; Duan, Y.-H.; Dai, Y.; Bao, Y.; Hu, M.; Zhou, Y.-Q.; Li, M.; Jiang, F.; Zhou, H.; Yao, X.-S.; Zhang, X.-K. Modulation of the Nur77-Bcl-2 Apoptotic Pathway by P38α MAPK. Oncotarget 2017, 8 (41), 69731– 69745, DOI: 10.18632/oncotarget.19227[Crossref], [PubMed], [CAS], Google Scholar372https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7isFWgug%253D%253D&md5=3325814a1b6136e56d94274201b0373aModulation of the Nur77-Bcl-2 apoptotic pathway by p38α MAPKLiu Jie; Wang Guang-Hui; Bao Yuzhou; Hu Mengjie; Zhou Yu-Qi; Li Mingyu; Jiang Fuquan; Zhou Hu; Zhang Xiao-Kun; Duan Ying-Hui; Dai Yi; Yao Xin-Sheng; Zhang Xiao-KunOncotarget (2017), 8 (41), 69731-69745 ISSN:.Orphan nuclear receptor Nur77 promotes apoptosis by targeting mitochondria through interaction with Bcl-2, an event that converts Bcl-2 from a survival to killer. However, how the Nur77-Bcl-2 apoptotic pathway is regulated remains largely unknown. In this study, we examined the regulation of the Nur77-Bcl-2 pathway by CCE9, a xanthone compound. Our results demonstrated that the apoptotic effect of CCE9 depended on its induction of Nur77 expression, cytoplasmic localization, and mitochondrial targeting. The activation of the Nur77-Bcl-2 pathway by CCE9 was associated with its activation of p38α MAPK. Inhibition of p38α MAPK activation by knocking down or knocking out p38α MAPK impaired the effect of CCE9 on inducing apoptosis and the expression and cytoplasmic localization of Nur77. In addition, CCE9 activation of p38α MAPK resulted in Bcl-2 phosphorylation and Bcl-2 interaction with Nur77, whereas inhibition of p38α MAPK activation or expression suppressed the interaction. Moreover, mutating Ser87 and Thr56 in the loop of Bcl-2, which are known to be phosphorylated by p38α MAPK, impaired the ability Bcl-2 to interact with Nur77. Together, our results reveal a profound role of p38α MAPK in regulating the Nur77-Bcl-2 apoptotic pathway through its modulation of Nur77 expression, Bcl-2 phosphorylation, and their interaction.
- 369Yao, L.-M.; He, J.-P.; Chen, H.-Z.; Wang, Y.; Wang, W.-J.; Wu, R.; Yu, C.-D.; Wu, Q. Orphan Receptor TR3 Participates in Cisplatin-Induced Apoptosis via Chk2 Phosphorylation to Repress Intestinal Tumorigenesis. Carcinogenesis 2012, 33 (2), 301– 311, DOI: 10.1093/carcin/bgr287[Crossref], [PubMed], [CAS], Google Scholar373https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVGisLk%253D&md5=9d6ce1a6cc34129c7c1a9800aff17e0cOrphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesisYao, Lu-ming; He, Jian-ping; Chen, Hang-zi; Wang, Yuan; Wang, Wei-jia; Wu, Rong; Yu, Chun-dong; Wu, QiaoCarcinogenesis (2012), 33 (2), 301-311CODEN: CRNGDP; ISSN:0143-3334. (Oxford University Press)Cisplatin is a widely used antitumor agent that induces aggressive cancer cell death via triggering cellular proteins involved in apoptosis. Here, we demonstrate that cisplatin effectively induces orphan nuclear receptor TR3 phosphorylation by activating Chk2 kinase activity and promoting cross talk between these 2 proteins, thereby contributing to the repression of intestinal tumorigenesis via apoptosis. Mechanistic anal. has demonstrated that Chk2-induced phosphorylation enables TR3 to bind to its response elements on the promoters of the BRE and RNF-7 genes, leading to the neg. regulation of these 2 anti-apoptotic genes. Furthermore, the induction of apoptosis by cisplatin is mediated by TR3, and knockdown of TR3 reduces cisplatin-induced apoptosis in colon cancer cells by 27%. The role of TR3 in cisplatin chemotherapy is further clarified in mouse models. In Apcmin/+ mice, cisplatin inhibits intestinal tumorigenesis by 70% in a TR3 phosphorylation-dependent manner; however, the loss of TR3 function in Apcmin/+/TR3-/- mice leads to the failure of cisplatin-induced repression of tumorigenesis. Consistently, xenografts derived from TR3 knockdown colon cancer cells are insensitive to cisplatin treatment, whereas a significant curative effect (50% inhibition) is obsd. in xenografts with functional TR3. Taken together, our study reveals a novel cross talk between Chk2 and TR3 and sheds light on the mechanism of cisplatin-induced apoptosis through TR3. Therefore, TR3 may be a new target of cisplatin for colon cancer therapy.
- 370Qi, H.; Jiang, Z.; Wang, C.; Yang, Y.; Li, L.; He, H.; Yu, Z. Sensitization of Tamoxifen-Resistant Breast Cancer Cells by Z-Ligustilide through Inhibiting Autophagy and Accumulating DNA Damages. Oncotarget 2017, 8 (17), 29300– 29317, DOI: 10.18632/oncotarget.16832[Crossref], [PubMed], [CAS], Google Scholar374https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1crgtVSrsw%253D%253D&md5=e58625798f05ea435727a8d80d699b93Sensitization of tamoxifen-resistant breast cancer cells by Z-ligustilide through inhibiting autophagy and accumulating DNA damagesQi Hongyi; Jiang Zhuyun; Wang Chengqiang; Yang Yi; Li Li; He Hui; Yu ZanyangOncotarget (2017), 8 (17), 29300-29317 ISSN:.Autophagy plays a pro-survival role in the tamoxifen-resistant breast cancer cells. Herein we found that autophagy was concomitantly induced in tamoxifen-resistant MCF-7 (MCF-7TR5) cells through the dissociation of Bcl-2 from Beclin 1 and subsequent enhancement of interaction among the ATG14-Beclin1-PI3KC3 complex. Moreover, higher level of DNA damage was observed in MCF-7TR5 cells with the decreased BRCA1 and RAD51 level and the increased Ku80 level. Interestingly, Nur77 was selectively degraded by autophagy, which causes the release of Ku80 from the Nur77-Ku80 complex, resulting in the increase of the DNA binding of Ku80 and DNA-PKcs. Meanwhile, Z-ligustilide, a phthalide compound from Radix Angelica sinensis, was shown to inhibit the autophagic flux by blocking the autophagosome-lysosome fusion. Importantly, Z-ligustilide-mediated autophagy inhibition restored Nur77 expression in MCF-7TR5 cells. Furthermore, Z-ligustilide promoted the interaction of Nur77 with Ku80 and thereby abolished the association of DNA-PKcs with DNA ends. Moreover, Z-ligustilide sensitized MCF-7TR5 cells in a caspase-independent cell death and enhanced the DNA damage caused by tamoxifen, which was found to be attenuated by shNur77. Together, these findings not only provide important insights into the formation of tamoxifen resistance in breast cancer cells, but also suggest Z-ligustilide may function as a novel autophagy inhibitor to overcome chemoresistance.
- 371Codina, A.; Benoit, G.; Gooch, J. T.; Neuhaus, D.; Perlmann, T.; Schwabe, J. W. R. Identification of a Novel Co-Regulator Interaction Surface on the Ligand Binding Domain of Nurr1 Using NMR Footprinting. J. Biol. Chem. 2004, 279 (51), 53338– 53345, DOI: 10.1074/jbc.M409096200[Crossref], [PubMed], [CAS], Google Scholar375https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVKqurfJ&md5=834e486a607271be30ace435e62ccb5fIdentification of a Novel Co-regulator Interaction Surface on the Ligand Binding Domain of Nurr1 Using NMR FootprintingCodina, Anna; Benoit, Gerard; Gooch, John T.; Neuhaus, David; Perlmann, Thomas; Schwabe, John W. R.Journal of Biological Chemistry (2004), 279 (51), 53338-53345CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The nuclear receptor Nurr1 is a transcription factor essential for the development of midbrain dopaminergic neurons in vertebrates. Recent crystal structures of the Nurr1 ligand binding domain (LBD) and the Drosophila orthologue dHR38 revealed that, although these receptors share the classical LBD architecture, they lack a ligand binding cavity. This vol. is instead filled with bulky hydrophobic side chains. Furthermore the "canonical" non-polar co-regulator binding groove is filled with polar side chains; thus, the regulation of transcription by this sub-family of nuclear receptor LBDs may be mediated by some other interaction surface on the LBD. We report here the identification of a novel co-regulator interface on the LBD of Nurr1. We used an NMR footprinting strategy that facilitates the identification of an interaction surface without the need of a full assignment. We found that non-polar peptides derived from the co-repressors SMRT and NCoR bind to a hydrophobic patch on the LBD of Nurr1. This binding surface involves a groove between helixes 11 and 12. Mutations in this site abolish activation by the Nurr1 LBD. These findings give insight into the unique mechanism of action of this class of nuclear receptors.
- 372Volakakis, N.; Malewicz, M.; Kadkhodai, B.; Perlmann, T.; Benoit, G. Characterization of the Nurr1 Ligand-Binding Domin Co-Activator Interaction Surface. J. Mol. Endocrinol. 2006, 37 (2), 317– 326, DOI: 10.1677/jme.1.02106[Crossref], [PubMed], [CAS], Google Scholar376https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1eju7vK&md5=edf8570136cd3cc79d05db7f4114d95eCharacterization of the Nurr1 ligand-binding domain co-activator interaction surfaceVolakakis, Nikolaos; Malewicz, Michal; Kadkhodai, Banafsheh; Perlmann, Thomas; Benoit, GerardJournal of Molecular Endocrinology (2006), 37 (2), 317-326CODEN: JMLEEI; ISSN:0952-5041. (Society for Endocrinology)The recently solved crystal structure of the orphan nuclear receptor (NR) Nurr1 ligand-binding domain (LBD) showed that Nurr1 lacks a cavity for ligand binding and a canonical NR co-activator-binding site. Computer modeling of the Nurr1 LBD structure identified a hydrophobic region on the surface of the Nurr1 LBD that was positioned on the opposite side from the classical co-activator-binding site. Site-directed mutagenesis demonstrated that this region is crit. for the activity of the Nurr1 LBD. Most mutations introduced in this region reduced or abolished transcriptional activity of the Nurr1 LBD, but mutation at lysine (K577) resulted in a drastically increased activity. Moreover, the activity of the Nurr1 LBD was shown to correlate with a propensity for proteasome-dependent degrdn. revealing a close assocn. between activity and Nurr1 protein turnover. These data provide novel insights into the mechanisms of transcription via the Nurr1 LBD and identify an alternative co-activator-binding surface that is unique to the NR4A family of NRs.
- 373Galleguillos, D.; Vecchiola, A.; Fuentealba, J. A.; Ojeda, V.; Alvarez, K.; Gómez, A.; Andrés, M. E. PIASγ Represses the Transcriptional Activation Induced by the Nuclear Receptor Nurr1. J. Biol. Chem. 2004, 279 (3), 2005– 2011, DOI: 10.1074/jbc.M308113200[Crossref], [PubMed], [CAS], Google Scholar377https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisF2qtQ%253D%253D&md5=154c65f97c2dc753bff88f5f35c74c00PIASγ represses the transcriptional activation induced by the nuclear receptor Nurr1Galleguillos, Danny; Vecchiola, Andrea; Fuentealba, Jose Antonio; Ojeda, Viviana; Alvarez, Karin; Gomez, Andrea; Andres, Maria EstelaJournal of Biological Chemistry (2004), 279 (3), 2005-2011CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Nurr1 is a transcription factor essential for the development of ventral dopaminergic neurons. In search for regulatory mechanisms of Nurr1 function, we identified the SUMO (small ubiquitin-like modifier)-E3 ubiquitin-protein isopeptide ligase, PIASγ, as an interaction partner of Nurr1. Overexpressed PIASγ and Nurr1 co-localize in the nuclei of transfected cells, and their interaction is demonstrated through co-immunopptn. and glutathione S-transferase pulldown assays. Co-expression of PIASγ with Nurr1 results in a potent repression of Nurr1-dependent transcriptional activation of an artificial NGFI-B response element (NBRE) reporter as well as of a reporter driven by the native tyrosine hydroxylase promoter. We identified two consensus sumoylation sites in Nurr1. The substitution of lysine 91 by arginine in one SUMO site enhanced the transcriptional activity of Nurr1, whereas the substitution of lysine 577 by arginine in the second SUMO site decreased transcriptional activity of Nurr1. Interestingly, PIASγ-induced repression of Nurr1 activity does not require the two sumoylation sites, because each mutant is repressed as efficiently as the wild type Nurr1. In addn., the mutations do not alter Nurr1 nuclear localization. Finally, we provide evidence that Nurr1 and PIASγ co-exist in several nuclei of the rodent central nervous system by demonstrating the co-expression of Nurr1 protein and PIASγ mRNA in the same cells. In conclusion, our studies identified PIASγ as a transcriptional co-regulator of Nurr1 and suggest that this interaction may have a physiol. role in regulating the expression of Nurr1 target genes.
- 374Zetterström, R. H.; Solomin, L.; Jansson, L.; Hoffer, B. J.; Olson, L.; Perlmann, T. Dopamine Neuron Agenesis in Nurr1-Deficient Mice. Science 1997, 276 (5310), 248– 250, DOI: 10.1126/science.276.5310.248[Crossref], [PubMed], [CAS], Google Scholar378https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3kvVKgtw%253D%253D&md5=d43da1dfc9d7266ff0c6ad72c453c8a1Dopamine neuron agenesis in Nurr1-deficient miceZetterstrom R H; Solomin L; Jansson L; Hoffer B J; Olson L; Perlmann TScience (New York, N.Y.) (1997), 276 (5310), 248-50 ISSN:0036-8075.Dopamine neurons of the substantia nigra and ventral tegmental area regulate movement and affective behavior and degenerate in Parkinson's disease. The orphan nuclear receptor Nurr1 was shown to be expressed in developing dopamine neurons before the appearance of known phenotypic markers for these cells. Mice lacking Nurr1 failed to generate midbrain dopaminergic neurons, were hypoactive, and died soon after birth. Nurr1 expression continued into adulthood, and brains of heterozygous animals, otherwise apparently healthy, contained reduced dopamine levels. These results suggest that putative Nurr1 ligands may be useful for treatment of Parkinson's disease and other disorders of midbrain dopamine circuitry.
- 375Wallén, Å.; Zetterström, R. H.; Solomin, L.; Arvidsson, M.; Olson, L.; Perlmann, T. Fate of Mesencephalic AHD2-Expressing Dopamine Progenitor Cells in Nurr1Mutant Mice. Exp. Cell Res. 1999, 253 (2), 737– 746, DOI: 10.1006/excr.1999.4691[Crossref], [PubMed], [CAS], Google Scholar379https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXns1ams7s%253D&md5=a7c93f4ac4dc7ff067dda4b0a81c6e49Fate of Mesencephalic AHD2-Expressing Dopamine Progenitor Cells in Nurr1 Mutant MiceWallen, Aasa; Zetterstrom, Rolf H.; Solomin, Ludmila; Arvidsson, Mariette; Olson, Lars; Perlmann, ThomasExperimental Cell Research (1999), 253 (2), 737-746CODEN: ECREAL; ISSN:0014-4827. (Academic Press)The orphan nuclear receptor NURR1 was previously demonstrated to be required for the generation of mesencephalic dopamine (DA) cells. However, even in the absence of NURR1, which is normally expressed as cells become postmitotic, neuronal differentiation is induced and expression of several genes detected in developing dopamine cells appears normal during early stages of development. These include the homeobox transcription factors engrailed and Ptx-3 as well as aldehyde dehydrogenase 2, here defined as the earliest marker identified in developing DA cells, expressed already in mitotic DA progenitors. The authors have used the expression of these dopaminergic markers, retrograde axonal tracing, and apoptosis analyses to study the fate of the DA progenitor cells in the absence of NURR1. The authors conclude that NURR1 plays a crit. role in the maturation, migration, striatal target area innervation, and survival of differentiating mesencephalic DA cells. (c) 1999 Academic Press.
- 376Smits, S. M.; Ponnio, T.; Conneely, O. M.; Burbach, J. P. H.; Smidt, M. P. Involvement of Nurr1 in Specifying the Neurotransmitter Identity of Ventral Midbrain Dopaminergic Neurons. Eur. J. Neurosci. 2003, 18 (7), 1731– 1738, DOI: 10.1046/j.1460-9568.2003.02885.x[Crossref], [PubMed], [CAS], Google Scholar380https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3srks12ntQ%253D%253D&md5=fe0562191d66ada0636016078fcd1611Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neuronsSmits Simone M; Ponnio Tiia; Conneely Orla M; Burbach J Peter H; Smidt Marten PThe European journal of neuroscience (2003), 18 (7), 1731-8 ISSN:0953-816X.The mesencephalic dopaminergic (mesDA) system is involved in many brain functions including motor control and motivated behaviour, and is of clinical importance because of its implication in psychiatric disorders and Parkinson's disease. Nurr1, a member of the nuclear hormone receptor superfamily of transcription factors, is essential for establishing the dopaminergic phenotype, because expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, requires Nurr1. In addition, Nurr1 plays an important role in the maintenance of mesDA neurons. Neonatal Nurr1 knockout mice lack expression of the dopamine transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and l-aromatic amino acid decarboxylase (AADC) in addition to TH specifically in mesDA neurons. It is unclear whether the lack of expression of these dopaminergic markers is caused by a maintenance defect or whether the induction of these markers depends on Nurr1 expression. To address this problem, the expression of DAT, VMAT2 and AADC was analysed at embryonic day 12.5 and 14.5. Here we demonstrate that induction of VMAT2 and DAT specifically in mesDA neurons requires Nurr1 expression, whereas AADC expression in mesDA neurons is induced independently of Nurr1 function.
- 377Hermanson, E.; Joseph, B.; Castro, D.; Lindqvist, E.; Aarnisalo, P.; Wallén, Å.; Benoit, G.; Hengerer, B.; Olson, L.; Perlmann, T. Nurr1 Regulates Dopamine Synthesis and Storage in MN9D Dopamine Cells. Exp. Cell Res. 2003, 288 (2), 324– 334, DOI: 10.1016/S0014-4827(03)00216-7[Crossref], [PubMed], [CAS], Google Scholar381https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmt1ehurg%253D&md5=21af82cbad4208df496aa2044cf8c510Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cellsHermanson, Elisabet; Joseph, Bertrand; Castro, Diogo; Lindqvist, Eva; Aarnisalo, Piia; Wallen, Asa; Benoit, Gerard; Hengerer, Bastian; Olson, Lars; Perlmann, ThomasExperimental Cell Research (2003), 288 (2), 324-334CODEN: ECREAL; ISSN:0014-4827. (Elsevier Science)Nurr1, a transcription factor belonging to the nuclear receptor family, is essential for the generation of midbrain dopamine (DA) cells during embryonic development. Nurr1 continues to be expressed in adult DA neurons but the role for Nurr1 in inducing and regulating basic dopaminergic functions such as dopamine synthesis and storage has remained unknown. The authors have previously used MN9D dopamine cells to analyze the role of Nurr1 and retinoids in DA cell maturation. These studies demonstrated that both Nurr1 and retinoids induce cell cycle arrest and a mature morphol. Here the authors used MN9D cells to investigate how Nurr1 regulates dopaminergic functions. The authors' results demonstrate that Nurr1, but not retinoids, increases DA content and the expression of arom. L-amino acid decarboxylase (AADC) and vesicular monoamine transporter-2 (VMAT2) in MN9D cells. In a Nurr1-inducible cell line upregulation of VMAT2 is dependent on continuous Nurr1 expression. Moreover, AADC and VMAT2 are deregulated in midbrain DA cells of Nurr1 knockout embryos as revealed by in situ hybridization. Together, the results provide evidence indicating an instructive role for Nurr1 in controlling DA synthesis and storage.
- 378Jacobs, F. M. J.; van der Linden, A. J. A.; Wang, Y.; von Oerthel, L.; Sul, H. S.; Burbach, J. P. H.; Smidt, M. P. Identification of Dlk1, Ptpru and Klhl1 as Novel Nurr1 Target Genes in Meso-Diencephalic Dopamine Neurons. Development 2009, 136 (14), 2363– 2373, DOI: 10.1242/dev.037556[Crossref], [PubMed], [CAS], Google Scholar382https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpvFGgtbw%253D&md5=5670ef9db289ea3357c06fc3cb9f8c39Identification of Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in meso-diencephalic dopamine neuronsJacobs, Frank M. J.; van der Linden, Annemarie J. A.; Wang, Yuhui; von Oerthel, Lars; Sul, Hei Sook; Burbach, J. Peter H.; Smidt, Marten P.Development (Cambridge, United Kingdom) (2009), 136 (14), 2363-2373CODEN: DEVPED; ISSN:0950-1991. (Company of Biologists Ltd.)The orphan nuclear receptor Nurr1 is essential for the development of meso-diencephalic dopamine (mdDA) neurons and is required, together with the homeobox transcription factor Pitx3, for the expression of genes involved in dopamine metab. To elucidate the mol. mechanisms that underlie the neuronal deficits in Nurr1-/- mice, the authors performed combined gene expression microarrays and ChIP-on-chip anal. and thereby identified Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in vivo. In line with the previously described cooperativity between Nurr1 and Pitx3, the authors show that the expression of Ptpru and Klhl1 in mdDA neurons is also dependent on Pitx3. Furthermore, the authors demonstrate that Nurr1 interacts with the Ptpru promoter directly and requires Pitx3 for full expression of Ptpru in mdDA neurons. By contrast, the expression of Dlk1 is maintained in Pitx3-/- embryos and is even expanded into the rostral part of the mdDA area, suggesting a unique position of Dlk1 in the Nurr1 and Pitx3 transcriptional cascades. Expression anal. in Dlk1-/- embryos reveals that Dlk1 is required to prevent premature expression of Dat in mdDA neuronal precursors as part of the multifaceted process of mdDA neuronal differentiation driven by Nurr1 and Pitx3. Taken together, the involvement of Nurr1 and Pitx3 in the expression of novel target genes involved in important neuronal processes such as neuronal patterning, axon outgrowth and terminal differentiation, opens up new avenues to study the properties of mdDA neurons during development and in neuronal pathol. as obsd. in Parkinson's disease.
- 379Gil, M.; McKinney, C.; Lee, M. K.; Eells, J. B.; Phyillaier, M. A.; Nikodem, V. M. Regulation of GTP Cyclohydrolase I Expression by Orphan Receptor Nurr1 in Cell Culture and in Vivo. J. Neurochem. 2007, 101 (1), 142– 150, DOI: 10.1111/j.1471-4159.2006.04356.x[Crossref], [PubMed], [CAS], Google Scholar383https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXksFSqsbs%253D&md5=fd52963bb097c5a8fead9538497f3743Regulation of GTP cyclohydrolase I expression by orphan receptor Nurr1 in cell culture and in vivoGil, Minchan; McKinney, Cushla; Lee, Mi Kyeong; Eells, Jeffrey B.; Phyillaier, Marcia A.; Nikodem, Vera M.Journal of Neurochemistry (2007), 101 (1), 142-150CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)Nurr1 is an orphan nuclear transcription factor essential for the terminal differentiation of dopamine (DA) neurons in the ventral midbrain (VM). To identify the Nurr1-target genes, we carried out microarray and quant. real-time PCR analyses of Nurr1 null and wild-type mice in VM at embryonic day (E) 12.5 and shortly after birth (P0). In addn. to the absence of mRNAs of DA synthesizing enzymes, the GTP (GTP) cyclohydrolase I (GTPCH) was also substantially reduced in the VM of Nurr1-null mice. GTPCH is the first enzyme in the synthesis pathway of tetrahydrobiopterin (BH4), an essential cofactor for tyrosine hydroxylase in DA synthesis. In the mouse, Nurr1 and GTPCH mRNA were first detected at E10.5, and GTPCH transcription paralleled that of Nurr1. Small interfering RNA targeted against Nurr1 decreases GTPCH expression in MC3T3-E1 osteoblasts in cell culture. Cotransfection of Nurr1 and the GTPCH-luciferase (luc) reporter increased the luc activity by about threefold in N2A cells. Addnl. anal. using 5'-deletions and mutants revealed that Nurr1 activates GTPCH transcription indirectly through the proximal promoter region, in the absence of the nerve growth factor-induced clone B (NGFI-B) responsive element-like sites, similarly, as recently reported for DA transporter regulation by Nurr1.
- 380Luo, Y.; Henricksen, L. A.; Giuliano, R. E.; Prifti, L.; Callahan, L. M.; Federoff, H. J. VIP Is a Transcriptional Target of Nurr1 in Dopaminergic Cells. Exp. Neurol. 2007, 203 (1), 221– 232, DOI: 10.1016/j.expneurol.2006.08.005[Crossref], [PubMed], [CAS], Google Scholar384https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1Krt73O&md5=2f4c1bf011cc81bb73c3e7e601c9d1b5VIP is a transcriptional target of Nurr1 in dopaminergic cellsLuo, Yu; Henricksen, Leigh A.; Giuliano, Rita E.; Prifti, Llanda; Callahan, Linda M.; Federoff, Howard J.Experimental Neurology (2007), 203 (1), 221-232CODEN: EXNEAC; ISSN:0014-4886. (Elsevier)The orphan nuclear receptor Nurr1 is required for the development of the ventral mesencephalic dopaminergic neurons. These are the same neurons that are invariantly lost in patients with Parkinson's disease. Nurr1 mRNA expression is not confined to the developing midbrain, and yet Nurr1 appears to be essential for either the maturation of progenitors into fully post-mitotic dopaminergic neurons and/or once formed, their survival. The function of Nurr1 in the transactivation of gene(s) important for neuronal development and/or maintenance is uncharacterized. To characterize potential downstream target genes of Nurr1, we sought to identify mRNAs that are differentially affected by Nurr1 expression. Using a dopaminergic cell line in which Nurr1 content was tightly regulated, differential display anal. identified transcripts altered by Nurr1 expression, including the mRNA encoding vasoactive intestinal peptide (VIP). Herein, we demonstrate that Nurr1 regulates VIP mRNA and protein levels, and transactivates the VIP promoter through Nurr1-responsive cis elements. In addn., dopaminergic cells release and utilize VIP to mediate survival when challenged with paraquat. Nurr1 regulation of VIP is also demonstrated in vivo as loss of Nurr1 function results in diminished VIP mRNA levels within the developing midbrain.
- 381Wallén, Å.; Castro, D. S.; Zetterström, R. H.; Karlén, M.; Olson, L.; Ericson, J.; Perlmann, T. Orphan Nuclear Receptor Nurr1 Is Essential for Ret Expression in Midbrain Dopamine Neurons and in the Brain Stem. Mol. Cell. Neurosci. 2001, 18 (6), 649– 663, DOI: 10.1006/mcne.2001.1057[Crossref], [PubMed], [CAS], Google Scholar385https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXptFegtbc%253D&md5=c1a76324ad2202dcf2cba48ff75e0ea4Orphan Nuclear Receptor Nurr1 Is Essential for Ret Expression in Midbrain Dopamine Neurons and in the Brain StemWallen, Asa; Castro, Diogo S.; Zetterstroem, Rolf H.; Karlen, Mattias; Olson, Lars; Ericson, Johan; Perlmann, ThomasMolecular and Cellular Neuroscience (2001), 18 (6), 649-663CODEN: MOCNED; ISSN:1044-7431. (Academic Press)The orphan nuclear receptor Nurr1 is essential for development of midbrain dopamine (DA) cells. In Nurr1-deficient mice, DA precursor cells fail to migrate normally, are unable to innervate target areas, and only transiently express DA cell marker genes. In the search for Nurr1-regulated genes that might explain this developmental phenotype, the authors found that expression of the receptor tyrosine kinase Ret is deregulated in these cells of Nurr1-deficient embryos. In addn., the authors' analyses establish Nurr1 as an early marker for the dorsal motor nucleus (DMN) of the vagus nerve. Interestingly, Ret expression is absent also in these cells in Nurr1-targeted mice. Neuronal innervation of vagus nerve target areas appeared normal apart from a subtle disorganization of the DMN-derived nerve fibers. In conclusion, regulation of Ret by Nurr1 in midbrain DA neurons and in the DMN has implications for both embryonal development and adult physiol. in which signaling by neurotrophic factors plays important roles. (c) 2001 Academic Press.
- 382Heng, X.; Jin, G.; Zhang, X.; Yang, D.; Zhu, M.; Fu, S.; Li, X.; Le, W. Nurr1 Regulates Top IIβ and Functions in Axon Genesis of Mesencephalic Dopaminergic Neurons. Mol. Neurodegener. 2012, 7 (1), 4, DOI: 10.1186/1750-1326-7-4[Crossref], [PubMed], [CAS], Google Scholar386https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotFKqtLc%253D&md5=04ed715adc18a156f0b28a887f8ab862Nurr1 regulates Top IIβ and functions in axon genesis of mesencephalic dopaminergic neuronsHeng, Xin; Jin, Gang; Zhang, Xin; Yang, Dehuang; Zhu, Mingzhe; Fu, Shijun; Li, Xuping; Le, WeidongMolecular Neurodegeneration (2012), 7 (), 4CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)Background: NURR1 (also named as NR4A2) is a member of the steroid/thyroid hormone receptor family, which can bind to DNA and modulate expression of target genes. Previous studies have shown that NURR1 is essential for the nigral dopaminergic neuron phenotype and function maintenance and the defects of the gene are possibly assocd. with Parkinson's disease (PD). Results: In this study, we used new born Nurr1 knock-out mice combined with Affymetrix genechip technol. and real time polymerase chain reaction (PCR) to identify Nurr1 regulated genes, which led to the discovery of several transcripts differentially expressed in the nigro-striatal pathway of Nurr1 knock-out mice. We found that an axon genesis gene called Topoisomerase IIβ (Top IIβ) was down-regulated in Nurr1 knock-out mice and we identified two functional NURR1 binding sites in the proximal Top IIβ promoter. While in Top IIβ null mice, we saw a significant loss of dopaminergic neurons in the substantial nigra and lack of neurites along the nigro-striatal pathway. Using specific TOP II antagonist ICRF-193 or Top IIβ siRNA in the primary cultures of ventral mesencephalic (VM) neurons, we documented that suppression of TOP IIβ expression resulted in VM neurites shortening and growth cones collapsing. Furthermore, microinjection of ICRF-193 into the mouse medial forebrain bundle (MFB) led to the loss of nigro-striatal projection. Conclusion: Taken together, our findings suggest that Top IIβ might be a down-stream target of Nurr1, which might influence the processes of axon genesis in dopaminergic neurons via the regulation of TOP IIβ expression. The Nurr1-Top IIβ interaction may shed light on the pathol. role of Nurr1 defect in the nigro-striatal pathway deficiency assocd. with PD.
- 383Montarolo, F.; Martire, S.; Perga, S.; Spadaro, M.; Brescia, I.; Allegra, S.; De Francia, S.; Bertolotto, A. NURR1 Deficiency Is Associated to ADHD-like Phenotypes in Mice. Transl. Psychiatry 2019, 9 (1), 207, DOI: 10.1038/s41398-019-0544-0[Crossref], [PubMed], [CAS], Google Scholar387https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3Mrit1KhsQ%253D%253D&md5=90bfd9ffda4c02f020121bd232b1d303NURR1 deficiency is associated to ADHD-like phenotypes in miceMontarolo Francesca; Martire Serena; Perga Simona; Spadaro Michela; Bertolotto Antonio; Montarolo Francesca; Martire Serena; Perga Simona; Spadaro Michela; Bertolotto Antonio; Montarolo Francesca; Perga Simona; Brescia Irene; Allegra Sarah; De Francia SilviaTranslational psychiatry (2019), 9 (1), 207 ISSN:.The transcription factor NURR1 regulates the dopamine (DA) signaling pathway and exerts a critical role in the development of midbrain dopaminergic neurons (mDA). NURR1 alterations have been linked to DA-associated brain disorders, such as Parkinson's disease and schizophrenia. However, the association between NURR1 defects and the attention-deficit hyperactivity disorder (ADHD), a DA-associated brain disease characterized by hyperactivity, impulsivity and inattention, has never been demonstrated. To date, a comprehensive murine model of ADHD truly reflecting the whole complex human psychiatric disorder still does not exist. NURR1-knockout (NURR1-KO) mice have been reported to exhibit increased spontaneous locomotor activity, but their complete characterization is still lacking. In the present study a wide-ranging test battery was used to perform a comprehensive analysis of the behavioral phenotype of the male NURR1-KO mice. As a result, their hyperactive phenotype was confirmed, while their impulsive behavior was reported for the first time. On the other hand, no anxiety and alterations in motor coordination, sociability and memory were observed. Also, the number of mDA expressing tyrosine hydroxylase, a rate-limiting enzyme of catecholamines biosynthesis, and DA level in brain were not impaired in NURR1-KO mice. Finally, hyperactivity has been shown to be recovered by treatment with methylphenidate, the first line psychostimulant drug used for ADHD. Overall, our study suggests that the NURR1 deficient male mouse may be a satisfactory model to study some ADHD behavioral phenotypes and to test the clinical efficacy of potential therapeutic agents.
- 384McCoy, J. M.; Walkenhorst, D. E.; McCauley, K. S.; Elaasar, H.; Everett, J. R.; Mix, K. S. Orphan Nuclear Receptor NR4A2 Induces Transcription of the Immunomodulatory Peptide Hormone Prolactin. J. Inflammation 2015, 12, 13, DOI: 10.1186/s12950-015-0059-2[Crossref], [CAS], Google Scholar388https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MrptVOitA%253D%253D&md5=5418e7c9413369471ffa90d4bee47bb6Orphan nuclear receptor NR4A2 induces transcription of the immunomodulatory peptide hormone prolactinMcCoy Joseph M; Walkenhorst Dana E; McCauley Keegan S; Elaasar Hiba; Everett Jordan R; Mix Kimberlee SJournal of inflammation (London, England) (2015), 12 (), 13 ISSN:1476-9255.BACKGROUND: Nuclear receptor 4A2 (NR4A2) is an orphan nuclear receptor and constitutively active transcription factor expressed at elevated levels in inflamed joint tissues from patients with arthritis. Inflammatory mediators rapidly and potently induce NR4A2 expression in resident joint cells and infiltrating immune cells. This receptor promotes synovial hyperplasia by increasing proliferation of synoviocytes and inducing transcription of matrix degrading enzymes and pro-inflammatory mediators. In order to further elucidate the molecular mechanisms of NR4A2, we conducted a gene expression screen to identify novel transcriptional targets of NR4A2 that may contribute to arthritis progression. METHODS: NR4A2 was over-expressed in human synoviocytes by lentiviral transduction and gene expression changes were measured using qPCR arrays specific for inflammation, proliferation, adhesion, and migration pathways. Subsequent analysis focused on the most potently induced gene prolactin (PRL). Messenger RNA levels of PRL and PRL receptor (PRL-R) were measured by RT-qPCR and protein levels were measured by ELISA. PRL promoter studies were conducted in synoviocytes transiently transfected with NR4A2 and PRL reporter constructs. Molecular responses to PRL in synoviocytes were addressed using qPCR arrays specific for JAK/STAT signaling pathways. RESULTS: PRL was the most potently induced gene on the qPCR arrays, exhibiting a 68-fold increase in response to ectopic NR4A2. This gene encodes an immunomodulatory peptide hormone with roles in autoimmune diseases and inflammation. Induction of PRL mRNA and secreted protein by NR4A2 was confirmed in subsequent experiments, with increases of 300-fold and 18-fold respectively. Depletion of endogenous NR4A receptors with shRNA reduced basal and PGE2-induced PRL levels by 95%. At the transcriptional level, NR4A2 requires a functional DNA binding domain to transactivate the distal PRL promoter. Deletional analysis indicates that NR4A2 targets a region of the distal PRL promoter spanning -270 to -32 bp. In synoviocytes, recombinant PRL regulates several genes involved in inflammation, proliferation, and cell survival, suggesting that NR4A2 induced PRL may also impact these pathways and contribute to arthritis progression. CONCLUSIONS: These results provide the first evidence for transcriptional regulation of the immunomodulatory peptide hormone PRL by NR4A2 in synoviocytes, and highlight a novel molecular pathway in inflammatory arthritis.
- 385Safe, S.; Jin, U. H.; Morpurgo, B.; Abudayyeh, A.; Singh, M.; Tjalkens, R. B. Nuclear Receptor 4A (NR4A) Family - Orphans No More. J. Steroid Biochem. Mol. Biol. 2016, 157, 48– 60, DOI: 10.1016/j.jsbmb.2015.04.016[Crossref], [PubMed], [CAS], Google Scholar389https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnt1Wjs7k%253D&md5=1dbc9721e70c9f19ea72032a60d351feNuclear receptor 4A (NR4A) family - orphans no moreSafe, Stephen; Jin, Un-Ho; Morpurgo, Benjamin; Abudayyeh, Ala; Singh, Mandip; Tjalkens, Ronald B.Journal of Steroid Biochemistry and Molecular Biology (2016), 157 (), 48-60CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)The orphan nuclear receptors NR4A1, NR4A2 and NR4A3 are immediate early genes induced by multiple stressors, and the NR4A receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurol. functions and also in inflammation and inflammatory diseases and in immune functions and cancer. Despite the similarities of NR4A1, NR4A2 and NR4A3 and their interactions with common cis-genomic elements, they exhibit unique activities and cell-/tissue-specific functions. Although endogenous ligands for NR4A receptors have not been identified, there is increasing evidence that structurally-diverse synthetic mols. can directly interact with the ligand binding domain of NR4A1 and act as agonists or antagonists, and ligands for NR4A2 and NR4A3 have also been identified. Since NR4A receptors are key factors in multiple diseases, there are opportunities for the future development of NR4A ligands for clin. applications in treating multiple health problems including metabolic, neurol. and cardiovascular diseases, other inflammatory conditions, and cancer.
- 386Decressac, M.; Volakakis, N.; Björklund, A.; Perlmann, T. NURR1 in Parkinson Disease - From Pathogenesis to Therapeutic Potential. Nat. Rev. Neurol. 2013, 9 (11), 629– 636, DOI: 10.1038/nrneurol.2013.209[Crossref], [PubMed], [CAS], Google Scholar390https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1ChsrjJ&md5=0ccc0530d53c1d19ef38e81307b99691NURR1 in Parkinson disease-from pathogenesis to therapeutic potentialDecressac, Mickael; Volakakis, Nikolaos; Bjoerklund, Anders; Perlmann, ThomasNature Reviews Neurology (2013), 9 (11), 629-636CODEN: NRNACP; ISSN:1759-4758. (Nature Publishing Group)A review. In Parkinson disease (PD), affected midbrain dopamine (DA) neurons lose specific dopaminergic properties before the neurons die. How the phenotype of DA neurons is normally established and the ways in which pathol. affects the maintenance of cell identity are, therefore, important considerations. Orphan nuclear receptor NURR1 (NURR1, also known as NR4A2) is involved in the differentiation of midbrain DA neurons, but also has an important role in the adult brain. Emerging evidence indicates that impaired NURR1 function might contribute to the pathogenesis of PD: NURR1 and its transcriptional targets are downregulated in midbrain DA neurons that express high levels of the disease-causing protein α-synuclein. Clin. and exptl. data indicate that disrupted NURR1 function contributes to induction of DA neuron dysfunction, which is seen in early stages of PD. The likely involvement of NURR1 in the development and progression of PD makes this protein a potentially interesting target for therapeutic intervention.
- 387Liu, H.; Liu, H.; Li, T.; Cui, J.; Fu, Y.; Ren, J.; Sun, X.; Jiang, P.; Yu, S.; Li, C. NR4A2 Genetic Variation and Parkinson’s Disease: Evidence from a Systematic Review and Meta-Analysis. Neurosci. Lett. 2017, 650, 25– 32, DOI: 10.1016/j.neulet.2017.01.062[Crossref], [PubMed], [CAS], Google Scholar391https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmtVymsLo%253D&md5=bf8113ddd6ffc1cd79ee68fcdca001baNR4A2 genetic variation and Parkinson's disease: Evidence from a systematic review and meta-analysisLiu, Hongmei; Liu, Hongbo; Li, Ting; Cui, Jiayi; Fu, Yingmei; Ren, Juanjuan; Sun, Xiujia; Jiang, Ping; Yu, Shunying; Li, ChunboNeuroscience Letters (2017), 650 (), 25-32CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)The homo sapiens nuclear receptor subfamily 4, group A (NR4A2) genetic variation has been implicated as a risk factor for Parkinson's disease (PD). Nevertheless, the results are inconclusive. We conducted a comprehensive systematic review and meta-anal. to quantify the impact of NR4A2 variation on the risk of PD.all eligible case-control studies published up to June 2016 by searching Pubmed, OVID, EBSCO, PsycINFO, ISI Web of Knowledge, Chinese Biomedical Literature Database and China Academic Journals Database were identified. Pooled odds ratio (OR) with 95% confidence interval (CI) were used to access the strength of the assocn. in fixed- or random-effects model.eighteen studies reported 24 genetic variants with a total of 6150 cases and 5919 controls were included. Twelve studies for NR4A2 rs35479735 polymorphism and 4 studies for rs12803 were available for meta-anal. A significant assocn. was obsd. for rs35479735 under the homozygous model (OR = 1.31, 95% CI: 1.10-1.56, P = 0.003), whereas no significant assocn. for rs12803 was detected. In subgroup anal. stratified by ethnicity, age onset and familial history, we found no significant assocn. except one in sporadic PD subgroup under the recessive (OR = 3.30, 95% CI: 1.23-8.84, P = 0.02) and homozygous model (OR = 3.43, 95% CI: 1.26-9.33, P = 0.02) for rs35479735.the study comprehensively evaluated the assocn. of NR4A2 variation with PD, and the results failed to demonstrate that the NR4A2 polymorphisms significantly assocd. with PD except for rs35479735, suggesting that more studies are needed to elucidate if NR4A2 is a risk of PD.
- 388Chu, Y.; Le, W.; Kompoliti, K.; Jankovic, J.; Mufson, E. J.; Kordower, J. H. Nurr1 in Parkinson’s Disease and Related Disorders. J. Comp. Neurol. 2006, 494 (3), 495– 514, DOI: 10.1002/cne.20828[Crossref], [PubMed], [CAS], Google Scholar392https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MnkvFCksA%253D%253D&md5=6cd609068c9d0996f1f8ee27a991ccc6Nurr1 in Parkinson's disease and related disordersChu Yaping; Le Weidong; Kompoliti Katie; Jankovic Joseph; Mufson Elliott J; Kordower Jeffrey HThe Journal of comparative neurology (2006), 494 (3), 495-514 ISSN:0021-9967.In mammals, the transcription factor Nurr1 is expressed early in development and continues to be detectable throughout the organism's lifetime. Nurr1 is involved in the establishment and maintenance of the dopaminergic phenotype within specific central nervous system neuronal subpopulations including the nigrostriatal dopamine system. This protein is reduced over the course of normal aging, which is a major risk factor for Parkinson's disease (PD). However, whether Nurr1 expression is affected by PD has not been documented. The present study examined the role of Nurr1 in the maintenance of the dopaminergic phenotype within neurons in substantia nigra in PD compared with patients with diagnoses of progressive supranuclear palsy (PSP) or Alzheimer's disease (AD) or age-matched-matched controls. In PD, the optical density (OD) of Nurr1 immunofluorescence was significantly decreased in nigral neurons containing alpha-synuclein-immunoreactive inclusions. Similarly, the OD of Nurr1 immunofluorescence intensity in the nigra of AD cases was decreased in neurons with neurofibrillary tangles (NFTs). In contrast to PD and AD, the OD of Nurr1 immunofluorescence intensity was severely decreased in the neurons with or without NFTs in PSP cases. Decline of Nurr1-ir neuronal number and OD was observed within substantia nigra (SN) neurons in PD but not within hippocampal neurons. The decline in Nurr1-ir expression was correlated with loss of tyrosine hydroxylase immunofluorescence across the four groups. These data demonstrate that Nurr1 deficiency in dopaminergic neurons is associated with the intracellular pathology in both synucleinopathies and tauopathies.
- 389Decressac, M.; Kadkhodaei, B.; Mattsson, B.; Laguna, A.; Perlmann, T.; Björklund, A. α-Synuclein-Induced down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons. Sci. Transl. Med. 2012, 4 (163), 163ra156, DOI: 10.1126/scitranslmed.3004676
- 390Liu, W.; Gao, Y.; Chang, N. Nurr1 Overexpression Exerts Neuroprotective and Anti-Inflammatory Roles via down-Regulating CCL2 Expression in Both in Vivo and in Vitro Parkinson’s Disease Models. Biochem. Biophys. Res. Commun. 2017, 482 (4), 1312– 1319, DOI: 10.1016/j.bbrc.2016.12.034[Crossref], [PubMed], [CAS], Google Scholar394https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFSnsL%252FE&md5=7cd2714b6d711f34e2e1c3a90d6b692dNurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 expression in both in vivo and in vitro Parkinson's disease modelsLiu, Wei; Gao, Yang; Chang, NaBiochemical and Biophysical Research Communications (2017), 482 (4), 1312-1319CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)The abnormality of nuclear receptor-related protein 1 (Nurr1) in expression and function can contribute to neurodegeneration of dopaminergic neurons and occurrence of Parkinson's disease (PD). However, its related mechanism in PD is still unknown. In this study, we found that Nurr1 was down-regulated and CCL2 was up-regulated in PD patients and PD mice. CCL2 promoted apoptosis and secretion of TNF-α and IL-1β in SH-SY5Y cells and inhibited cell viability while knockdown of CCL2 exerted the opposite effects. Nurr1 overexpression inhibited apoptosis, the release of TNF-α and IL-1β and promoted viability in α-Syn-treated SH-SY5Y cells, which was markedly promoted by CCL2 antibody and dramatically reversed by CCL2. Nurr1 overexpression neg. regulated CCL2 expression in vivo and in vitro. Furthermore, Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits and played neuroprotective and anti-inflammatory roles in MPTP-induced PD mice by down-regulating CCL2 in vivo. In conclusion, Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 in both in vivo and in vitro PD models, contributing to developing mechanism-based and neuroprotective strategies against PD.
- 391Volakakis, N.; Tiklova, K.; Decressac, M.; Papathanou, M.; Mattsson, B.; Gillberg, L.; Nobre, A.; Björklund, A.; Perlmann, T. Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression. J. Neurosci. 2015, 35 (42), 14370– 14385, DOI: 10.1523/JNEUROSCI.1155-15.2015[Crossref], [PubMed], [CAS], Google Scholar395https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xjt1Ggsr8%253D&md5=02952a6cfed6d9883e4b2358c72617d2Nurr1 and retinoid X receptor ligands stimulate Rt signaling in dopamine neurons and can alleviate α-synuclein disrupted gene expressionVolakakis, Nikolaos; Tiklova, Katarina; Decressac, Mickael; Papathanou, Maria; Mattsson, Bengt; Gillberg, Linda; Nobre, Andre; Bjoerklund, Anders; Perlmann, ThomasJournal of Neuroscience (2015), 35 (42), 14370-14385CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)α-Synuclein, a protein enriched in Lewy bodies and highly implicated in neurotoxicity in Parkinson's disease, is distributed both at nerve terminals and in the cell nucleus. Here we show that a nuclear deriv. of α-synuclein induces more pronounced changes at the gene expression level in mouse primary dopamine (DA) neurons compared to a deriv. that is excluded from the nucleus. Moreover, by RNA sequencing we analyzed the extent of genome-wide effects on gene expression resulting from expression of human α-synuclein in primary mouse DA neurons. The results implicated the transcription factor Nurr1 as a key dysregulated target of α-synuclein toxicity. Forced Nurr1 expression restored the expression of hundreds of dysregulated genes in primary DA neurons expressing α-synuclein, and therefore prompted us to test the possibility that Nurr1 can be pharmacol. targeted by bexarotene, a ligand for the retinoid X receptor that forms heterodimers with Nurr1. Although our data demonstrated that bexarotene was ineffective in neuroprotection in rats in vivo, the results revealed that bexarotene has the capacity to coregulate subsets of Nurr1 target genes including the receptor tyrosine kinase subunit Ret. Moreover, bexarotene was able to restore dysfunctional Ret-dependent neurotrophic signaling in α-synuclein-overexpressing mouse DA neurons. These data highlight the role of the Nurr1-Ret signaling pathway as a target of α-synuclein toxicity and suggest that retinoid X receptor ligands with appropriate pharmacol. properties could have therapeutic potential in Parkinson's disease.
- 392Volakakis, N.; Kadkhodaei, B.; Joodmardi, E.; Wallis, K.; Panman, L.; Silvaggi, J.; Spiegelman, B. M.; Perlmann, T. NR4A Orphan Nuclear Receptors as Mediators of CREB-Dependent Neuroprotection. Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (27), 12317– 12322, DOI: 10.1073/pnas.1007088107[Crossref], [PubMed], [CAS], Google Scholar396https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovFyitb0%253D&md5=94e36bdc05c59c8212b562ec4fd265cfNR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotectionVolakakis, Nikolaos; Kadkhodaei, Banafsheh; Joodmardi, Eliza; Wallis, Karin; Panman, Lia; Silvaggi, Jessica; Spiegelman, Bruce M.; Perlmann, ThomasProceedings of the National Academy of Sciences of the United States of America (2010), 107 (27), 12317-12322, S12317/1-S12317/16CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Induced expression of neuroprotective genes is essential for maintaining neuronal integrity after stressful insults to the brain. Here we show that NR4A nuclear orphan receptors are induced after excitotoxic and oxidative stress in neurons, up-regulate neuro-protective genes, and increase neuronal survival. Moreover, we show that NR4A proteins are induced by cAMP response element binding protein (CREB) in neurons exposed to stressful insults and that they function as mediators of CREB-induced neuronal survival. Animals with null mutations in three of six NR4A alleles show increased oxidative damage, blunted induction of neuroprotective genes, and increased vulnerability in the hippocampus after treatment with kainic acid. We also demonstrate that NR4A and the transcriptional coactivator PGC-1α independently regulate distinct CREB-dependent neuroprotective gene programs. These data identify NR4A nuclear orphan receptors as essential mediators of neuroprotection after exposure to neuropathol. stress.
- 393Wang, X.; Zhuang, W.; Fu, W.; Wang, X.; Lv, E.; Li, F.; Zhou, S.; Rausch, W.-D.; Wang, X. The Lentiviral-Mediated Nurr1 Genetic Engineering Mesenchymal Stem Cells Protect Dopaminergic Neurons in a Rat Model of Parkinson’s Disease. Am. J. Transl. Res. 2018, 10 (6), 1583– 1599[PubMed], [CAS], Google Scholar397https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFGlu7jM&md5=f36d4eced350c7b5845a2ad11692d612The lentiviral-mediated Nurr1 genetic engineering mesenchymal stem cells protect dopaminergic neurons in a rat model of Parkinson's diseaseWang, Xiaoxiao; Zhuang, Wenxin; Fu, Wenyu; Wang, Xiaocui; Lv, E.; Li, Fengjie; Zhou, Shuanhu; Rausch, Wolf-Dieter; Wang, XinAmerican Journal of Translational Research (2018), 10 (6), 1583-1599CODEN: AJTRA7; ISSN:1943-8141. (e-Century Publishing Corp.)Nuclear receptor-related factor 1 (Nurr1) has a crucial role in the development and maturation of mesencephalic dopamine (DA) neurons and also plays a protective role in maintenance of DA neurons by inhibiting the activation of microglia and astrocyte. Moreover, the mutations in Nurr1 gene are assocd. with familial Parkinson's disease (PD), suggested that Nurr1 modulation is a potential therapeutic target for PD. This study examines the therapeutic effects of transplantation of Nurr1 gene-modified bone marrow mesenchymal stem cells (MSCs) on 6-hydroxydopamine (6-OHDA)-induced PD rat models. MSCs were transduced with lentivirus expressing Nurr1 gene and then intrastriatally transplanted into PD rats. Our results showed that Nurr1 gene-modified MSCs overexpress and secrete Nurr1 protein in vitro and also survive and migrate in the brain. Four weeks after transplantation Nurr1 gene-modified MSCs dramatically ameliorated the abnormal behavior of PD rats and increased the nos. of tyrosine hydroxylase (TH)-pos. cells in the substantia nigra (SN) and TH-pos. fibers in the striatum, inhibited the activation of glial cells, and reduced the expression of inflammatory factors in the SN. Taken together, these findings suggest that intrastriatal transplantation of lentiviral vector mediated Nurr1 gene-modified MSCs has notable therapeutic effect for PD rats.
- 394Saijo, K.; Winner, B.; Carson, C. T.; Collier, J. G.; Boyer, L.; Rosenfeld, M. G.; Gage, F. H.; Glass, C. K. A Nurr1/CoREST Pathway in Microglia and Astrocytes Protects Dopaminergic Neurons from Inflammation-Induced Death. Cell 2009, 137 (1), 47– 59, DOI: 10.1016/j.cell.2009.01.038[Crossref], [PubMed], [CAS], Google Scholar398https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXls1Srsro%253D&md5=7f2a912829a985550055d14cdb5fc9eeA Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced deathSaijo, Kaoru; Winner, Beate; Carson, Christian T.; Collier, Jana G.; Boyer, Leah; Rosenfeld, Michael G.; Gage, Fred H.; Glass, Christopher K.Cell (Cambridge, MA, United States) (2009), 137 (1), 47-59CODEN: CELLB5; ISSN:0092-8674. (Cell Press)Nurr1, an orphan nuclear receptor, plays an essential role in the generation and maintenance of dopaminergic neurons in the brain. Rare mutations in Nurr1 are assocd. with familial Parkinson's disease, but the underlying basis for this relationship has not been established. Here, we demonstrate that Nurr1 unexpectedly functions to inhibit expression of pro-inflammatory neurotoxic mediators in both microglia and astrocytes. Reduced Nurr1 expression results in exaggerated inflammatory responses in microglia that are further amplified by astrocytes, leading to the prodn. of factors that cause death of tyrosine hydroxylase-expressing neurons. Nurr1 exerts anti-inflammatory effects by docking to NF-κB-p65 on target inflammatory gene promoters in a signal-dependent manner. Subsequently, Nurr1 recruits the CoREST corepressor complex, resulting in clearance of NF-κB-p65 and transcriptional repression. These studies suggest that Nurr1 protects against loss of dopaminergic neurons in Parkinson's disease in part by limiting the prodn. of neurotoxic mediators by microglia and astrocytes.
- 395Yi, S.-H.; He, X.-B.; Rhee, Y.-H.; Park, C.-H.; Takizawa, T.; Nakashima, K.; Lee, S.-H. Foxa2 Acts as a Co-Activator Potentiating Expression of the Nurr1-Induced DA Phenotype via Epigenetic Regulation. Development 2014, 141 (4), 761– 772, DOI: 10.1242/dev.095802[Crossref], [PubMed], [CAS], Google Scholar399https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvV2nsbw%253D&md5=e62a83e3762aadea0924652011a0609fFoxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulationYi, Sang-Hoon; He, Xi-Biao; Rhee, Yong-Hee; Park, Chang-Hwan; Takizawa, Takumi; Nakashima, Kinichi; Lee, Sang-HunDevelopment (Cambridge, United Kingdom) (2014), 141 (4), 761-772CODEN: DEVPED; ISSN:0950-1991. (Company of Biologists Ltd.)Understanding how dopamine (DA) phenotypes are acquired in midbrain DA (mDA) neuron development is important for bioassays and cell replacement therapy for mDA neuron-assocd. disorders. Here, we demonstrate a feed-forward mechanism of mDA neuron development involving Nurr1 and Foxa2. Nurr1 acts as a transcription factor for DA phenotype gene expression. However, Nurr1-mediated DA gene expression was inactivated by forming a protein complex with CoREST, and then recruiting histone deacetylase 1 (Hdac1), an enzyme catalyzing histone deacetylation, to DA gene promoters. Co-expression of Nurr1 and Foxa2 was established in mDA neuron precursor cells by a pos. cross-regulatory loop. In the presence of Foxa2, the Nurr1-CoREST interaction was diminished (by competitive formation of the Nurr1-Foxa2 activator complex), and CoREST-Hdac1 proteins were less enriched in DA gene promoters. Consequently, histone 3 acetylation (H3Ac), which is responsible for open chromatin structures, was strikingly increased at DA phenotype gene promoters. These data establish the interplay of Nurr1 and Foxa2 as the crucial determinant for DA phenotype acquisition during mDA neuron development.
- 396Kim, C.-H.; Han, B.-S.; Moon, J.; Kim, D.-J.; Shin, J.; Rajan, S.; Nguyen, Q. T.; Sohn, M.; Kim, W.-G.; Han, M.; Jeong, I.; Kim, K.-S.; Lee, E.-H.; Tu, Y.; Naffin-Olivos, J. L.; Park, C.-H.; Ringe, D.; Yoon, H. S.; Petsko, G. A.; Kim, K.-S. Nuclear Receptor Nurr1 Agonists Enhance Its Dual Functions and Improve Behavioral Deficits in an Animal Model of Parkinson’s Disease. Proc. Natl. Acad. Sci. U. S. A. 2015, 112 (28), 8756– 8761, DOI: 10.1073/pnas.1509742112[Crossref], [PubMed], [CAS], Google Scholar400https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVOrs7%252FL&md5=715bbb21e39675989c84aa2ab51447dcNuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson's diseaseKim, Chun-Hyung; Han, Baek-Soo; Moon, Jisook; Kim, Deog-Joong; Shin, Joon; Rajan, Sreekanth; Nguyen, Quoc Toan; Sohn, Mijin; Kim, Won-Gon; Han, Minjoon; Jeong, Inhye; Kim, Kyoung-Shim; Lee, Eun-Hye; Tu, Yupeng; Naffin-Olivos, Jacqueline L.; Park, Chang-Hwan; Ringe, Dagmar; Yoon, Ho Sup; Petsko, Gregory A.; Kim, Kwang-SooProceedings of the National Academy of Sciences of the United States of America (2015), 112 (28), 8756-8761CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Parkinson's disease (PD), primarily caused by selective degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting 1-2% of the global population over the age of 65. Currently available pharmacol. treatments are largely symptomatic and lose their efficacy over time with accompanying severe side effects such as dyskinesia. Thus, there is an unmet clin. need to develop mechanism-based and/or disease-modifying treatments. Based on the unique dual role of the nuclear orphan receptor Nurr1 for development and maintenance of mDA neurons and their protection from inflammation-induced death, we hypothesize that Nurr1 can be a mol. target for neuroprotective therapeutic development for PD. Here we show successful identification of Nurr1 agonists sharing an identical chem. scaffold, 4-amino-7-chloroquinoline, suggesting a crit. structure-activity relationship. In particular, we found that two antimalarial drugs, amodiaquine and chloroquine stimulate the transcriptional function of Nurr1 through phys. interaction with its ligand binding domain (LBD). Remarkably, these compds. were able to enhance the contrasting dual functions of Nurr1 by further increasing transcriptional activation of mDA-specific genes and further enhancing transrepression of neurotoxic proinflammatory gene expression in microglia. Importantly, these compds. significantly improved behavioral deficits in 6-hydroxydopamine lesioned rat model of PD without any detectable signs of dyskinesia-like behavior. These findings offer proof of principle that small mols. targeting the Nurr1 LBD can be used as a mechanism-based and neuroprotective strategy for PD.
- 397Rajan, S.; Jang, Y.; Kim, C.-H.; Kim, W.; Toh, H. T.; Jeon, J.; Song, B.; Serra, A.; Lescar, J.; Yoo, J. Y.; Beldar, S.; Ye, H.; Kang, C.; Liu, X.-W.; Feitosa, M.; Kim, Y.; Hwang, D.; Goh, G.; Lim, K.-L.; Park, H. M.; Lee, C. H.; Oh, S. F.; Petsko, G. A.; Yoon, H. S.; Kim, K.-S. PGE1 and PGA1 Bind to Nurr1 and Activate Its Transcriptional Function. Nat. Chem. Biol. 2020, 16, 876– 886, DOI: 10.1038/s41589-020-0553-6[Crossref], [PubMed], [CAS], Google Scholar401https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVSgsLzI&md5=5e726ca7eff0e5ed8216d4d4bc99b4e9PGE1 and PGA1 bind to Nurr1 and activate its transcriptional functionRajan, Sreekanth; Jang, Yongwoo; Kim, Chun-Hyung; Kim, Woori; Toh, Hui Ting; Jeon, Jeha; Song, Bin; Serra, Aida; Lescar, Julien; Yoo, Jun Yeob; Beldar, Serap; Ye, Hong; Kang, Congbao; Liu, Xue-Wei; Feitosa, Melissa; Kim, Yeahan; Hwang, Dabin; Goh, Geraldine; Lim, Kah-Leong; Park, Hye Min; Lee, Choong Hwan; Oh, Sungwhan F.; Petsko, Gregory A.; Yoon, Ho Sup; Kim, Kwang-SooNature Chemical Biology (2020), 16 (8), 876-886CODEN: NCBABT; ISSN:1552-4450. (Nature Research)The orphan nuclear receptor Nurr1 is crit. for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallog. structure of Nurr1-LBD bound to PGA1 at 2.05 Å resoln. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson's disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1's transcriptional function.
- 398Bruning, J. M.; Wang, Y.; Oltrabella, F.; Tian, B.; Kholodar, S. A.; Liu, H.; Bhattacharya, P.; Guo, S.; Holton, J. M.; Fletterick, R. J.; Jacobson, M. P.; England, P. M. Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite. Cell Chem. Biol. 2019, 26 (5), 674– 685, DOI: 10.1016/j.chembiol.2019.02.002[Crossref], [PubMed], [CAS], Google Scholar402https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXks1SitLw%253D&md5=9d083c1ceca8cfb134b566ac191ef810Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine MetaboliteBruning, John M.; Wang, Yan; Oltrabella, Francesca; Tian, Boxue; Kholodar, Svetlana A.; Liu, Harrison; Bhattacharya, Paulomi; Guo, Su; Holton, James M.; Fletterick, Robert J.; Jacobson, Matthew P.; England, Pamela M.Cell Chemical Biology (2019), 26 (5), 674-685.e6CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)Nurr1, a nuclear receptor essential for the development, maintenance, and survival of midbrain dopaminergic neurons, is a potential therapeutic target for Parkinson's disease, a neurol. disorder characterized by the degeneration of these same neurons. Efforts to identify Nurr1 agonists have been hampered by the recognition that it lacks several classic regulatory elements of nuclear receptor function, including the canonical ligand-binding pocket. Here we report that the dopamine metabolite 5,6-dihydroxyindole (DHI) binds directly to and modulates the activity of Nurr1. Using biophys. assays and X-ray crystallog., we show that DHI binds to the ligand-binding domain within a non-canonical pocket, forming a covalent adduct with Cys566. In cultured cells and zebrafish, DHI stimulates Nurr1 activity, including the transcription of target genes underlying dopamine homeostasis. These findings suggest avenues for developing synthetic Nurr1 ligands to ameliorate the symptoms and progression of Parkinson's disease.
- 399Smith, G. A.; Rocha, E. M.; Rooney, T.; Barneoud, P.; McLean, J. R.; Beagan, J.; Osborn, T.; Coimbra, M.; Luo, Y.; Hallett, P. J.; Isacson, O. A Nurr1 Agonist Causes Neuroprotection in a Parkinson’s Disease Lesion Model Primed with the Toll-Like Receptor 3 DsRNA Inflammatory Stimulant Poly(I:C). PLoS One 2015, 10 (3), e0121072, DOI: 10.1371/journal.pone.0121072[Crossref], [PubMed], [CAS], Google Scholar403https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1SjtrzP&md5=b39dab5808bf6d7f94b4a78b9a42088aA Nurr1 agonist causes neuroprotection in a Parkinson-s disease lesion model primed with the toll-like receptor 3 dsRNA inflammatory stimulant poly(I:C)Smith, Gaynor A.; Rocha, Emily M.; Rooney, Thomas; Barneoud, Pascal; McLean, Jesse R.; Beagan, Jonathan; Osborn, Teresia; Coimbra, Madeleine; Luo, Yongyi; Hallett, Penelope J.; Isacson, OlePLoS One (2015), 10 (3), e0121072/1-e0121072/14CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Dopaminergic neurons in the substantia nigra pars compacta (SNpc) are characterized by the expression of genes required for dopamine synthesis, handling and reuptake and the expression of these genes is largely controlled by nuclear receptor related 1 (Nurr1). Nurr1 is also expressed in astrocytes and microglia where it functions to mitigate the release of proinflammatory cytokines and neurotoxic factors. Given that Parkinson-s disease (PD) pathogenesis has been linked to both loss of Nurr1 expression in the SNpc and inflammation, increasing levels of Nurr1 maybe a promising therapeutic strategy. In this study a novel Nurr1 agonist, SA00025, was tested for both its efficiency to induce the transcription of dopaminergic target genes in vivo and prevent dopaminergic neuron degeneration in an inflammation exacerbated 6-OHDA-lesion model of PD. SA00025 (30mg/kg p.o.) entered the brain and modulated the expression of the dopaminergic phenotype genes TH, VMAT, DAT, AADC and the GDNF receptor gene c-Ret in the SN of naive rats. Daily gavage treatment with SA00025 (30mg/kg) for 32 days also induced partial neuroprotection of dopaminergic neurons and fibers in rats administered a priming injection of polyinosinic-polycytidylic acid (poly (I:C)) and subsequent injection of 6-OHDA. The neuroprotective effects of SA00025 in this dopamine neuron degeneration model were assocd. with changes in microglial morphol. indicative of a resting state and a decrease in microglial specific IBA-1 staining intensity in the SNpc. Astrocyte specific GFAP staining intensity and IL-6 levels were also reduced.We conclude that Nurr1 agonist treatment causes neuroprotective and anti-inflammatory effects in an inflammation exacerbated 6-OHDA lesion model of PD.
- 400Zhang, Z.; Li, X.; Xie, W.; Tuo, H.; Hintermann, S.; Jankovic, J.; Le, W. Anti-Parkinsonian Effects of Nurr1 Activator in Ubiquitin-Proteasome System Impairment Induced Animal Model of Parkinson’s Disease. CNS Neurol. Disord.: Drug Targets 2012, 11 (6), 768– 773, DOI: 10.2174/187152712803581155[Crossref], [PubMed], [CAS], Google Scholar404https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlvFShug%253D%253D&md5=8ef8133d1de395f58ecb0ca0813b6b1dAnti-Parkinsonian effects of Nurr1 activator in ubiquitin-proteasome system impairment induced animal model of Parkinson's diseaseZhang, Zhen; Li, Xuping; Xie, Wen-jie; Tuo, Houzhen; Hintermann, Samuel; Jankovic, Joseph; Le, WeidongCNS & Neurological Disorders: Drug Targets (2012), 11 (6), 768-773CODEN: CNDDA3; ISSN:1871-5273. (Bentham Science Publishers Ltd.)Nurr1 is a member of the nuclear receptor superfamily and is a potential susceptibility gene for Parkinson's disease (PD). Several lines of studies in vitro and in vivo reported that defects in the Nurr1 gene cause nigrostriatal neuronal deficiency as seen in PD. In the present study, we used a a synthetic low mol. wt. Nurr1 activator which increases the transcription of Nurr1 to investigate whether it has anti-parkinsonian effects against nigrostriatal neuronal degeneration induced by proteasome inhibitor lactacystin. Adult C57BL/6 mice were treated orally with the Nurr1 activator and an inactive structural analog as a control at a dose of 10mg/kg per day, starting 3 days before microinjection of proteasome inhibitor lactacystin into the medial forebrain bundle and the treatment continued for a total of 4 wk. Animal behavior tests, and pathol. and biochem. examns. were performed to det. the anti-parkinsonian effects of the Nurr1 activator. We found that treatment with the Nurr1 activator significantly improved rotarod performance, attenuated dopamine neuron loss and nigrostriatal dopamine redn., increased expression of Nurr1, dopamine transporter and vesicular monoamine transporter 2, and alleviated microglial activation in the substantia nigra of lactacystin-lesioned mice. These results suggest that the Nurr1 activator may become an innovative strategy for the treatment of PD.
- 401Friling, S.; Bergsland, M.; Kjellander, S. Activation of Retinoid X Receptor Increases Dopamine Cell Survival in Models for Parkinson’s Disease. BMC Neurosci. 2009, 10, 146, DOI: 10.1186/1471-2202-10-146[Crossref], [PubMed], [CAS], Google Scholar405https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c%252FgtVequg%253D%253D&md5=cff519f05c894958d1c4db4996c835fdActivation of Retinoid X Receptor increases dopamine cell survival in models for Parkinson's diseaseFriling Stina; Bergsland Maria; Kjellander SusannaBMC neuroscience (2009), 10 (), 146 ISSN:.BACKGROUND: Parkinson's disease (PD) is caused by degeneration of dopamine (DA) neurons in the ventral midbrain (vMB) and results in severely disturbed regulation of movement. The disease inflicts considerable suffering for the affected and their families. Today, the opportunities for pharmacological treatment are meager and new technologies are needed. Previous studies have indicated that activation of the nuclear receptor Retinoid X Receptor (RXR) provides trophic support for DA neurons. Detailed investigations of these neurotrophic effects have been hampered by the lack of readily available DA neurons in vitro. The aim of this study was to further describe the potential neurotrophic actions of RXR ligands and, for this and future purposes, develop a suitable in vitro-platform using mouse embryonic stem cells (mESCs). RESULTS: We studied the potential neurotrophic effects of the RXR ligand LG100268 (LG268) and the RXR-Nurr1 ligand XCT0139508 (XCT) in neuronal cultures derived from rat primary vMB and mESCs. RXR ligands protect DA neurons from stress, such as that induced by the PD-modeling toxin 6-hydroxy dopamine (6-OHDA) and hypoxia, but not from stress induced by oxidative hydrogen peroxide (H2O2) or the excitotoxic agent kainic acid (KA). The neurotrophic effect is selective for DA neurons. DA neurons from rat primary vMB and mESCs behaved similarly, but the mESC-derived cultures contained a much higher fraction of DA cells and thus provided more accessible experimental conditions. CONCLUSIONS: RXR ligands rescue DA neurons from degeneration caused by the PD simulating 6-OHDA as well as hypoxia. Thus, RXR is a novel promising target for PD research. mESC-derived DA cells provide a valid and accessible in vitro-platform for studying PD inducing toxins and potential trophic agents.
- 402Spathis, A. D.; Asvos, X.; Ziavra, D.; Karampelas, T.; Topouzis, S.; Cournia, Z.; Qing, X.; Alexakos, P.; Smits, L. M.; Dalla, C.; Rideout, H. J.; Schwamborn, J. C.; Tamvakopoulos, C.; Fokas, D.; Vassilatis, D. K. Nurr1:RXRα Heterodimer Activation as Monotherapy for Parkinson’s Disease. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (15), 3999– 4004, DOI: 10.1073/pnas.1616874114[Crossref], [PubMed], [CAS], Google Scholar406https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvF2itbc%253D&md5=b1336a176bdd412897decce66f281512Nurr1:RXRα heterodimer activation as monotherapy for Parkinson's diseaseSpathis, Athanasios D.; Asvos, Xenophon; Ziavra, Despina; Karampelas, Theodoros; Topouzis, Stavros; Cournia, Zoe; Qing, Xiaobing; Alexakos, Pavlos; Smits, Lisa M.; Dalla, Christina; Rideout, Hardy J.; Schwamborn, Jens Christian; Tamvakopoulos, Constantin; Fokas, Demosthenes; Vassilatis, Demetrios K.Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (15), 3999-4004CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead mol., which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), arom. L-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.
- 403Wang, J.; Bi, W.; Zhao, W.; Varghese, M.; Koch, R. J.; Walker, R. H.; Chandraratna, R. A.; Sanders, M. E.; Janesick, A.; Blumberg, B.; Ward, L.; Ho, L.; Pasinetti, G. M. Selective Brain Penetrable Nurr1 Transactivator for Treating Parkinson’s Disease. Oncotarget 2016, 7 (7), 7469– 7479, DOI: 10.18632/oncotarget.7191[Crossref], [PubMed], [CAS], Google Scholar407https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28npt1Kltg%253D%253D&md5=43691e016c1aacf4e616678ce2fd9d84Selective brain penetrable Nurr1 transactivator for treating Parkinson's diseaseWang Jun; Bi Weina; Zhao Wei; Varghese Merina; Ward Libby; Ho Lap; Pasinetti Giulio M; Wang Jun; Pasinetti Giulio M; Koch Rick J; Walker Ruth H; Chandraratna Roshantha A; Sanders Martin E; Janesick Amanda; Blumberg BruceOncotarget (2016), 7 (7), 7469-79 ISSN:.Parkinson's disease (PD) is one of the most common movement disorders, and currently there is no effective treatment that can slow disease progression. Preserving and enhancing DA neuron survival is increasingly regarded as the most promising therapeutic strategy for treating PD. IRX4204 is a second generation retinoid X receptor (RXR) agonist that has no cross reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPARγ. We found that IRX4204 promotes the survival and maintenance of nigral dopaminergic (DA) neurons in a dose-dependent manner in primary mesencephalic cultures. Brain bioavailability studies demonstrate that IRX4204 can cross the blood brain barrier and reach the brain at nM concentration. Oral administration of IRX4204 can activate nuclear receptor Nurr1 downstream signaling in the substantia nigra (SN) andattenuate neurochemical and motor deficits in a rat model of PD. Our study suggests that IRX4204 represents a novel, potent and selective pharmacological means to activate cellular RXR-Nurr1 signaling and promote SN DA neuron survival in PD prevention and/or treatment.
- 404Loppi, S.; Kolosowska, N.; Kärkkäinen, O.; Korhonen, P.; Huuskonen, M.; Grubman, A.; Dhungana, H.; Wojciechowski, S.; Pomeshchik, Y.; Giordano, M.; Kagechika, H.; White, A.; Auriola, S.; Koistinaho, J.; Landreth, G.; Hanhineva, K.; Kanninen, K.; Malm, T. HX600, a Synthetic Agonist for RXR-Nurr1 Heterodimer Complex, Prevents Ischemia-Induced Neuronal Damage. Brain, Behav., Immun. 2018, 73, 670– 681, DOI: 10.1016/j.bbi.2018.07.021[Crossref], [PubMed], [CAS], Google Scholar408https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVersLnN&md5=9a686dd51ea3f879dd049e4db8094e70HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damageLoppi, S.; Kolosowska, N.; Karkkainen, O.; Korhonen, P.; Huuskonen, M.; Grubman, A.; Dhungana, H.; Wojciechowski, S.; Pomeshchik, Y.; Giordano, M.; Kagechika, H.; White, A.; Auriola, S.; Koistinaho, J.; Landreth, G.; Hanhineva, K.; Kanninen, K.; Malm, T.Brain, Behavior, and Immunity (2018), 73 (), 670-681CODEN: BBIMEW; ISSN:0889-1591. (Elsevier)Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were assocd. with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.
- 405Jeon, S. G.; Yoo, A.; Chun, D. W.; Hong, S. B.; Chung, H.; Kim, J.-I.; Moon, M. The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-Related Pathogenesis. Aging Dis. 2020, 11 (3), 705– 724, DOI: 10.14336/AD.2019.0718[Crossref], [PubMed], [CAS], Google Scholar409https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38rltVyrsw%253D%253D&md5=e34f6be08fe475744e1a90dd443374daThe Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer's Disease-related PathogenesisJeon Seong Gak; Yoo Anji; Chun Dong Wook; Hong Sang Bum; Moon Minho; Chung Hyunju; Kim Jin-IlAging and disease (2020), 11 (3), 705-724 ISSN:2152-5250.Several studies have revealed that the transcription factor nuclear receptor related 1 (Nurr1) plays several roles not only in the regulation of gene expression related to dopamine synthesis, but also in alternative splicing, and miRNA targeting. Moreover, it regulates cognitive functions and protects against inflammation-induced neuronal death. In particular, the role of Nurr1 in the pathogenesis of Parkinson's disease (PD) has been well investigated; for example, it has been shown that it restores behavioral and histological impairments in PD models. Although many studies have evaluated the connection between Nurr1 and PD pathogenesis, the role of Nurr1 in Alzheimer's disease (AD) remain to be studied. There have been several studies describing Nurr1 protein expression in the AD brain. However, only a few studies have examined the role of Nurr1 in the context of AD. Therefore, in this review, we highlight the overall effects of Nurr1 under the neuropathologic conditions related to AD. Furthermore, we suggest the possibility of using Nurr1 as a therapeutic target for AD or other neurodegenerative disorders.
- 406Terzioglu-Usak, S.; Negis, Y.; Karabulut, D. S.; Zaim, M.; Isik, S. Cellular Model of Alzheimer’s Disease: Aβ1–42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIβ and Nurr1 Expression. Curr. Alzheimer Res. 2017, 14 (6), 636– 644, DOI: 10.2174/1567205014666170117103217[Crossref], [PubMed], [CAS], Google Scholar410https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnsl2htrs%253D&md5=aaa13f66aa6b9e3b4918b8c2e58de6d1Cellular Model of Alzheimer';s Disease: Aβ1-42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIβ and Nurr1 ExpressionTerzioglu-Usak, Sule; Negis, Yesim; Karabulut, Derya S.; Zaim, Merve; Isik, SevimCurrent Alzheimer Research (2017), 14 (6), 636-644CODEN: CARUBY; ISSN:1567-2050. (Bentham Science Publishers Ltd.)Background: DNA topoisomerase IIβ (topo IIβ) plays a crucial role in neural differentiation and axonogenesis. Inhibition of topo IIβ activity in vitro and in vivo results in shorter axons and increased DNA damage. These mol. events also involve in Alzheimer's disease (AD); however, the role of topo IIβ in the pathogenesis of AD remains to be elucidated. Objectives: We aimed to investigate the role of topo IIβ assocn. with Nuclear receptor related 1 protein (Nurr1) in the onset of AD. Methods: In vitro AD model was established by the incubation of fibrillar amyloid-β 1-42 (Aβ1-42) for 48 h with cultured cerebellar granule neurons (CGNs) isolated from post-natal eight-day rats. The regulatory role of topo IIβ on the transcription of Nurr1 was analyzed in topo IIβ silenced CGNs, and also topo IIβ silenced and overexpressed in a neurally-differentiated human mesenchymal (hMSC) cell line. Results: Aβ1-42 fibrils led to the upregulation of Presenilin1 and Cofilin1 genes as measured at mRNA levels and hyperphosphorylation of tau protein, all are distinctive characteristics of AD pathol. A significant decrease in topo IIβ expression at mRNA and protein levels and Nurr1 at mRNA level was also obsd. In both cell types, Nurr1 expression was dramatically down-regulated due to topo IIβ deficiency, and was increased in topo IIβ overexpressing hMSCs. Conclusion: Our findings suggest that topo IIβ could be a down-stream target of signaling pathways contributing to AD-like pathol. However, further studies must be carried out in vivo to elucidate the precise assocn. topo IIβ with AD.
- 407Parra-Damas, A.; Valero, J.; Chen, M.; España, J.; Martín, E.; Ferrer, I.; Rodríguez-Alvarez, J.; Saura, C. A. Crtc1 Activates a Transcriptional Program Deregulated at Early Alzheimer’s Disease-Related Stages. J. Neurosci. 2014, 34 (17), 5776– 5787, DOI: 10.1523/JNEUROSCI.5288-13.2014[Crossref], [PubMed], [CAS], Google Scholar411https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs12iu7rN&md5=acfaea8d2b4668d95355d3935f1acaf2Crtc1 activates a transcriptional program deregulated at early Alzheimer's disease-related stagesParra-Damas, Arnaldo; Valero, Jorge; Chen, Meng; Espana, Judit; Martin, Elsa; Ferrer, Isidro; Rodriguez-Alvarez, Jose; Saura, Carlos A.Journal of Neuroscience (2014), 34 (17), 5776-5787, 12 pp.CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Cognitive decline is assocd. with gene expression changes in the brain, but the transcriptional mechanisms underlying memory impairments in cognitive disorders, such as Alzheimer's disease (AD), are largely unknown. Here, we aimed to elucidate relevant mechanisms responsible for transcriptional changes underlying early memory loss in AD by examg. pathol., behavioral, and transcriptomic changes in control and mutant β-amyloid precursor protein (APPSw,Ind) transgenic mice during aging. Genome-wide transcriptome anal. using mouse microarrays revealed deregulation of a gene network related with neurotransmission, synaptic plasticity, and learning/memory in the hippocampus of APPSw,Ind mice after spatial memory training. Specifically, APPSw,Ind mice show changes on a cAMP-responsive element binding protein (CREB)-regulated transcriptional program dependent on the CREB-regulated transcription coactivator-1 (Crtc1). Interestingly, synaptic activity and spatial memory induces Crtc1 dephosphorylation (Ser151), nuclear translocation, and Crtc1-dependent transcription in the hippocampus, and these events are impaired in APPSw,Ind mice at early pathol. and cognitive decline stages. CRTC1-dependent genes and CRTC1 levels are reduced in human hippocampus at intermediate Braak III/IV pathol. stages. Importantly, adeno-assocd. viral-mediated Crtc1 overexpression in the hippocampus efficiently reverses Aβ-induced spatial learning and memory deficits by restoring a specific subset of Crtc1 target genes. Our results reveal a crit. role of Crtc1-dependent transcription on spatial memory formation and provide the first evidence that targeting brain transcriptome reverses memory loss in AD.
- 408Moon, M.; Jeong, I.; Kim, C.-H.; Kim, J.; Lee, P. K. J.; Mook-Jung, I.; Leblanc, P.; Kim, K.-S. Correlation between Orphan Nuclear Receptor Nurr1 Expression and Amyloid Deposition in 5XFAD Mice, an Animal Model of Alzheimer’s Disease. J. Neurochem. 2015, 132 (2), 254– 262, DOI: 10.1111/jnc.12935[Crossref], [PubMed], [CAS], Google Scholar412https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFCms7o%253D&md5=59854c397dcd6079a09cef6221d60ed5Correlation between orphan nuclear receptor Nurr1 expression and amyloid deposition in 5XFAD mice, an animal model of Alzheimer's diseaseMoon, Minho; Jeong, Inhye; Kim, Chun-Hyung; Kim, Jihong; Lee, Paula K. J.; Mook-Jung, Inhee; Leblanc, Pierre; Kim, Kwang-SooJournal of Neurochemistry (2015), 132 (2), 254-262CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)The functional roles of the orphan nuclear receptor, Nurr1, have been extensively studied and well established in the development and survival of midbrain dopamine neurons. As Nurr1 and other NR4A members are widely expressed in the brain in overlapping and distinct manners, it has been an open question whether Nurr1 has important function(s) in other brain areas. Recent studies suggest that up-regulation of Nurr1 expression is crit. for cognitive functions and/or long-term memory in forebrain areas including hippocampal formation. Questions remain about the assocn. between Nurr1 expression and Alzheimer's disease (AD) brain pathol. Here, using our newly developed Nurr1-selective antibody, we report that Nurr1 protein is prominently expressed in brain areas with Aβ accumulation, i.e., the subiculum and the frontal cortex, in the 5XFAD mouse and that Nurr1 is highly co-expressed with Aβ at early stages. Furthermore, the no. of Nurr1-expressing cells significantly declines in the 5XFAD mouse in an age-dependent manner, accompanied by increased plaque deposition. Thus, our findings suggest that altered expression of Nurr1 is assocd. with AD progression. Using our newly developed Nurr1-selective antibody, we show that Nurr1 protein is prominently expressed in brain areas accumulating amyloid-beta (Aβ) in the transgenic mouse model of Alzheimer's disease (AD) and that Nurr1 is highly co-expressed with Aβ at early stages (upper panel). Furthermore, in the AD brain the no. of Nurr1-expressing cells significantly declines in an age-dependent manner concomitant with increased Aβ accumulation (lower diagram) highlighting a possible Nurr1 involvement in AD pathol.
- 409Moon, M.; Jung, E. S.; Jeon, S. G.; Cha, M.-Y.; Jang, Y.; Kim, W.; Lopes, C.; Mook-Jung, I.; Kim, K.-S. Nurr1 (NR4A2) Regulates Alzheimer’s Disease-Related Pathogenesis and Cognitive Function in the 5XFAD Mouse Model. Aging Cell 2019, 18 (1), e12866, DOI: 10.1111/acel.12866
- 410Montarolo, F.; Raffaele, C.; Perga, S.; Martire, S.; Finardi, A.; Furlan, R.; Hintermann, S.; Bertolotto, A. Effects of Isoxazolo-Pyridinone 7e, a Potent Activator of the Nurr1 Signaling Pathway, on Experimental Autoimmune Encephalomyelitis in Mice. PLoS One 2014, 9 (9), e108791, DOI: 10.1371/journal.pone.0108791[Crossref], [PubMed], [CAS], Google Scholar414https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslegtbvP&md5=bdf7ca10afd4a66a10360bb2ef394c69Effects of isoxazolo-pyridinone 7e, a potent activator of the Nurr1 signaling pathway, on experimental autoimmune encephalomyelitis in miceMontarolo, Francesca; Raffaele, Chiara; Perga, Simona; Martire, Serena; Finardi, Annamaria; Furlan, Roberto; Hintermann, Samuel; Bertolotto, AntonioPLoS One (2014), 9 (9), e108791/1-e108791/9, 9 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Multiple sclerosis (MS) is an autoimmune chronic disease of the central nervous system (CNS) characterized by immune-mediated inflammation, demyelination and subsequent axonal damage. Gene expression profiling showed that Nurr1, an orphan nuclear receptor, is down-regulated in peripheral blood mononuclear cells of MS patients. Nurr1 exerts an anti-inflammatory role repressing the activity of the pro-inflammatory transcription factor NF-kB. Here, we report that the preventive treatment with isoxazolo-pyridinone 7e, an activator of Nurr1 signaling pathway, reduces the incidence and the severity of a MS murine model, i.e. exptl. autoimmune encephalomyelitis (EAE). The compd. is able to attenuate inflammation and neurodegeneration in spinal cords of EAE mice by an NF-kB pathway-dependent process.
- 411Montarolo, F.; Perga, S.; Martire, S.; Bertolotto, A. Nurr1 Reduction Influences the Onset of Chronic EAE in Mice. Inflammation Res. 2015, 64 (11), 841– 844, DOI: 10.1007/s00011-015-0871-4[Crossref], [PubMed], [CAS], Google Scholar415https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVGnsbnP&md5=c7891a722359a2dd2a405d6cf63feafbNurr1 reduction influences the onset of chronic EAE in miceMontarolo, Francesca; Perga, Simona; Martire, Serena; Bertolotto, AntonioInflammation Research (2015), 64 (11), 841-844CODEN: INREFB; ISSN:1023-3830. (Birkhaeuser Basel)Objective: Nurr1 plays anti-inflammatory functions in astrocytes/microglia. Gene expression anal. reveals Nurr1 down-regulation in PBMCs of MS patients that neg. correlates with disease aggressiveness. This study assesses the consequences of Nurr1 redn. in a MS model represented by EAE. Methods: EAE was induced in heterozygous Nurr1 knockout mice. Clin. course was evaluated during pre-symptomatic, acute, and chronic phases. Neurohistopathol. state was analyzed in spinal cord. Results and conclusions: Nurr1 defect induces early EAE onset and increases inflammatory infiltrates in spinal cord suggesting a Nurr1 role in the early phase of EAE.
- 412Raveney, B. J. E.; Oki, S.; Yamamura, T. Nuclear Receptor NR4A2 Orchestrates Th17 Cell-Mediated Autoimmune Inflammation via IL-21 Signalling. PLoS One 2013, 8 (2), e56595, DOI: 10.1371/journal.pone.0056595[Crossref], [PubMed], [CAS], Google Scholar416https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjs12ns70%253D&md5=28d53561792eb7d317402d0177cf359bNuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signallingRaveney, Ben J. E.; Oki, Shinji; Yamamura, TakashiPLoS One (2013), 8 (2), e56595CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)IL-17-producing CD4+ T helper 17 (Th17) cells are pathogenic in a range of human autoimmune diseases and corresponding animal models. We now demonstrate that such T cells infiltrating the target organ during the induction of exptl. autoimmune encephalomyelitis (EAE) and exptl. autoimmune uveoretinitis (EAU) specifically express NR4A2. Further, we reveal a crit. involvement of NR4A2 in Th17 cell functions and Th17 cell-driven autoimmune diseases. When NR4A2 expression was blocked with siRNA, full Th17 differentiation was prevented in vitro: although cells expressed the master Th17 regulator, RORγt, they expressed reduced levels of IL-23R and were unable to produce IL-17 and IL-21. Notably, Th17 differentiation in the absence of NR4A2 was restored by exogenous IL-21, indicating that NR4A2 controls full maturation of Th17 cells via autocrine IL-21 signalling. Preventing NR4A2 expression in vivo by systemic treatment with NR4A2-specific siRNA also reduced Th17 effector responses and furthermore protected mice from EAE induction. In addn., the lack of disease was assocd. with a redn. in autocrine IL-21 prodn. and IL-23R expression. Similar modulation of NR4A2 expression was also effective as an intervention, reversing established autoimmune responses and ameliorating clin. disease symptoms. Thus, NR4A2 appears to control Th17 differentiation and so plays an essential role in the development of Th17-mediated autoimmune disease. As NR4A2 is also upregulated during human autoimmune disease, targeting NR4A2 may provide a new therapeutic approach in treating autoimmune disease.
- 413Park, T.-Y.; Jang, Y.; Kim, W.; Shin, J.; Toh, H. T.; Kim, C.-H.; Yoon, H. S.; Leblanc, P.; Kim, K.-S. Chloroquine Modulates Inflammatory Autoimmune Responses through Nurr1 in Autoimmune Diseases. Sci. Rep. 2019, 9, 15559, DOI: 10.1038/s41598-019-52085-w[Crossref], [PubMed], [CAS], Google Scholar417https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MjivFSgtQ%253D%253D&md5=35dbd549295d279d78965131b945703dChloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseasesPark Tae-Yoon; Jang Yongwoo; Kim Woori; Kim Chun-Hyung; Leblanc Pierre; Kim Kwang-Soo; Shin Joon; Toh Hui Ting; Yoon Ho Sup; Kim Kwang-SooScientific reports (2019), 9 (1), 15559 ISSN:.For over a half-century the anti-malarial drug chloroquine (CQ) has been used as a therapeutic agent, alone or in combination, to treat autoimmune diseases. However, neither the underlying mechanism(s) of action nor their molecular target(s) are well defined. The orphan nuclear receptor Nurr1 (also known as NR4A2) is an essential transcription factor affecting the development and maintenance of midbrain dopaminergic neurons. In this study, using in vitro T cell differentiation models, we demonstrate that CQ activates TREG cell differentiation and induces Foxp3 gene expression in a Nurr1-dependent manner. Remarkably, CQ appears to induce Nurr1 function by two distinct mechanisms: firstly, by direct binding to Nurr1's ligand-binding domain and promoting its transcriptional activity and secondly by upregulation of Nurr1 expression through the CREB signaling pathway. In contrast, CQ suppressed gene expression and differentiation of pathogenic TH17 cells. Importantly, using a valid animal model of inflammatory bowel disease (IBD), we demonstrated that CQ promotes Foxp3 expression and differentiation of TREG cells in a Nurr1-dependent manner, leading to significant improvement of IBD-related symptoms. Taken together, these data suggest that CQ ameliorates autoimmune diseases via regulating Nurr1 function/expression and that Nurr1 is a promising target for developing effective therapeutics of human inflammatory autoimmune diseases.
- 414Willems, S.; Ohrndorf, J.; Kilu, W.; Heering, J.; Merk, D. Fragment-like Chloroquinolineamines Activate the Orphan Nuclear Receptor Nurr1 and Elucidate Activation Mechanisms. J. Med. Chem. 2021, 64 (5), 2659– 2668, DOI: 10.1021/acs.jmedchem.0c01779[ACS Full Text], [CAS], Google Scholar418https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXkvVOlt7s%253D&md5=9cfedae7c809996347491ee53c26edd1Fragment-like Chloroquinolineamines Activate the Orphan Nuclear Receptor Nurr1 and Elucidate Activation MechanismsWillems, Sabine; Ohrndorf, Julia; Kilu, Whitney; Heering, Jan; Merk, DanielJournal of Medicinal Chemistry (2021), 64 (5), 2659-2668CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The ligand-activated transcription factor nuclear receptor related-1 (Nurr1) exhibits great potential for neurodegenerative disease treatment, but potent Nurr1 modulators to further probe and validate the nuclear receptor as a therapeutic target are lacking. We have systematically studied the structure-activity relationship of the 4-amino-7-chloroquinoline scaffold contained in Nurr1 activators amodiaquine and chloroquine and discovered fragment-like analogs that activated Nurr1 in several cellular settings. The most active descendants promoted the transcriptional activity of Nurr1 on human response elements as monomer, homodimer, and heterodimer and markedly enhanced Nurr1-dependent gene expression in human astrocytes. As a tool to elucidate mechanisms involving in Nurr1 activation, these Nurr1 agonists induced robust recruitment of NCoR1 and NCoR2 co-regulators to the Nurr1 ligand binding domain and promoted Nurr1 dimerization. These findings provide important insights in Nurr1 regulation. The fragment-sized Nurr1 agonists are appealing starting points for medicinal chem. and valuable early Nurr1 agonist tools for pharmacol. and chem. biol.
- 415de Vera, I. M. S.; Giri, P. K.; Munoz-Tello, P.; Brust, R.; Fuhrmann, J.; Matta-Camacho, E.; Shang, J.; Campbell, S.; Wilson, H. D.; Granados, J.; Gardner, W. J. J.; Creamer, T. P.; Solt, L. A.; Kojetin, D. J. Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1. ACS Chem. Biol. 2016, 11 (7), 1795– 1799, DOI: 10.1021/acschembio.6b00037[ACS Full Text], [CAS], Google Scholar419https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmvVyhsLs%253D&md5=598f95ccc2051710ed6c2662c843d8f8Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1de Vera, Ian Mitchelle S.; Giri, Pankaj K.; Munoz-Tello, Paola; Brust, Richard; Fuhrmann, Jakob; Matta-Camacho, Edna; Shang, Jinsai; Campbell, Sean; Wilson, Henry D.; Granados, Juan; Gardner, William J.; Creamer, Trevor P.; Solt, Laura. A.; Kojetin, Douglas J.ACS Chemical Biology (2016), 11 (7), 1795-1799CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Nurr1/NR4A2 is an orphan nuclear receptor, and currently there are no known natural ligands that bind Nurr1. A recent metabolomics study identified unsatd. fatty acids, including arachidonic acid and docosahexaenoic acid (DHA), that interact with the ligand-binding domain (LBD) of a related orphan receptor, Nur77/NR4A1. However, the binding location and whether these ligands bind other NR4A receptors were not defined. Here, we show that unsatd. fatty acids also interact with the Nurr1 LBD, and soln. NMR spectroscopy reveals the binding epitope of DHA at its putative ligand-binding pocket. Biochem. assays reveal that DHA-bound Nurr1 interacts with high affinity with a peptide derived from PIASγ, a protein that interacts with Nurr1 in cellular exts., and DHA also affects cellular Nurr1 transactivation. This work is the first structural report of a natural ligand binding to a canonical NR4A ligand-binding pocket and indicates a natural ligand can bind and affect Nurr1 function.
- 416de Vera, I. M. S.; Munoz-Tello, P.; Zheng, J.; Dharmarajan, V.; Marciano, D. P.; Matta-Camacho, E.; Giri, P. K.; Shang, J.; Hughes, T. S.; Rance, M.; Griffin, P. R.; Kojetin, D. J. Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1. Structure 2019, 27 (1), 66– 77, DOI: 10.1016/j.str.2018.10.002[Crossref], [PubMed], [CAS], Google Scholar420https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFCgsb3N&md5=f7b412a0b24e32cfae48ad55661f7707Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1de Vera, Ian Mitchelle S.; Munoz-Tello, Paola; Zheng, Jie; Dharmarajan, Venkatasubramanian; Marciano, David P.; Matta-Camacho, Edna; Giri, Pankaj Kumar; Shang, Jinsai; Hughes, Travis S.; Rance, Mark; Griffin, Patrick R.; Kojetin, Douglas J.Structure (Oxford, United Kingdom) (2019), 27 (1), 66-77.e5CODEN: STRUE6; ISSN:0969-2126. (Elsevier Ltd.)Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no phys. space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using soln. NMR spectroscopy, hydrogen/deuterium exchange mass spectrometry, and mol. dynamics simulations, we show that the putative canonical Nurr1 LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystd. conformation to allow binding of unsatd. fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinson's disease and schizophrenia.
- 417Windshügel, B. Structural Insights into Ligand-Binding Pocket Formation in Nurr1 by Molecular Dynamics Simulations. J. Biomol. Struct. Dyn. 2019, 37 (17), 4651– 4657, DOI: 10.1080/07391102.2018.1559099[Crossref], [PubMed], [CAS], Google Scholar421https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1Klsbo%253D&md5=ca9af61cc9aed54dead720ac8c4faf0aStructural insights into ligand-binding pocket formation in Nurr1 by molecular dynamics simulationsWindshuegel, BjoernJournal of Biomolecular Structure and Dynamics (2019), 37 (17), 4651-4657CODEN: JBSDD6; ISSN:0739-1102. (Taylor & Francis Ltd.)The nuclear receptor Nurr1 (NR4A2) has been identified as a potential target for the treatment of Parkinson's disease. In contrast to most other nuclear receptors, the X-ray crystal structure of the Nurr1 ligand-binding domain (LBD) lacks any ligand-binding pocket (LBP). However, NMR spectroscopy measurements have revealed that the known Nurr1 agonist docosahexaenoic acid (DHA) binds to a region within the LBD that corresponds to the classical NR ligand-binding pocket (LBP). In order to investigate the structural dynamics of the Nurr1 LBD and to study potential LBP formation, the conformational space of the receptor was sampled using a mol. dynamics (MD) simulation. Docking of DHA into 50,000 LBD structures extd. from the simulation revealed the existence of a transient LBP that is capable to fully harbor the compd. The location of the identified pocket overlaps with the ligand-binding site suggested by NMR expts. Structural anal. of the protein-ligand complex showed that only modest structural rearrangements within the Nurr1 LBD are required for LBP formation. These findings may support structure-based drug discovery campaigns for the development of receptor-specific agonists.
- 418Lesuisse, D.; Malanda, A.; Peyronel, J. F.; Evanno, Y.; Lardenois, P.; De-Peretti, D.; Abécassis, P.-Y.; Barnéoud, P.; Brunel, P.; Burgevin, M.-C.; Cegarra, C.; Auger, F.; Dommergue, A.; Lafon, C.; Even, L.; Tsi, J.; Luc, T. P. H.; Almario, A.; Olivier, A.; Castel, M.-N.; Taupin, V.; Rooney, T.; Vigé, X. Development of a Novel NURR1/NOT Agonist from Hit to Lead and Candidate for the Potential Treatment of Parkinson’s Disease. Bioorg. Med. Chem. Lett. 2019, 29 (7), 929– 932, DOI: 10.1016/j.bmcl.2019.01.024[Crossref], [PubMed], [CAS], Google Scholar422https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjt1Sqtbg%253D&md5=20b882a19d4c0db9abf47f45dfbc8b61Development of a novel NURR1/NOT agonist from hit to lead and candidate for the potential treatment of Parkinson's diseaseLesuisse, Dominique; Malanda, Andre; Peyronel, Jean-Francois; Evanno, Yannick; Lardenois, Patrick; De-Peretti, Danielle; Abecassis, Pierre-Yves; Barneoud, Pascal; Brunel, Pascale; Burgevin, Marie-Claude; Cegarra, Celine; Auger, Florian; Dommergue, Amelie; Lafon, Corinne; Even, Luc; Tsi, Joanna; Luc, Thy Phuong Hieu; Almario, Antonio; Olivier, Anne; Castel, Marie-Noelle; Taupin, Veronique; Rooney, Thomas; Vige, XavierBioorganic & Medicinal Chemistry Letters (2019), 29 (7), 929-932CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)In the course of a program aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson's disease, a few hits from high throughput screening were identified and characterized. A combined optimization pointed to a very narrow and stringent structure activity relationship. A comprehensive program of optimization led to a potent and safe candidate drug displaying neuroprotective and anti-inflammatory activity in several in vitro and in vivo models.
- 419Almario Garcia, A.; Lardenois, P.; Olivier, A. Derivatives of 2-Aryl-6-Phenyl-Imid Azo [1, 2-α]Pyridines, Their Preparation and Their Therapeutic Use. WO2008/034974A1. Sanofi-Aventis, 2008.
- 420Malanda, A.; Abécassis, P.-Y.; Barnéoud, P.; Brunel, P.; Taupin, V.; Vigé, X.; Lesuisse, D. Data on Synthesis, ADME and Pharmacological Properties and Early Safety Pharmacology Evaluation of a Series of Novel NURR1/NOT Agonist Potentially Useful for the Treatment of Parkinson’s Disease. Data Br. 2019, 27, 104057, DOI: 10.1016/j.dib.2019.104057
- 421Dubois, C.; Hengerer, B.; Mattes, H. Identification of a Potent Agonist of the Orphan Nuclear Receptor Nurr1. ChemMedChem 2006, 1 (9), 955– 958, DOI: 10.1002/cmdc.200600078[Crossref], [PubMed], [CAS], Google Scholar425https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVCmu7o%253D&md5=cf81e4fdb1410b826f77479f61f0c30cIdentification of a potent agonist of the orphan nuclear receptor Nurr1Dubois, Celine; Hengerer, Bastian; Mattes, HenriChemMedChem (2006), 1 (9), 955-958CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Mimotope's SynPhase double lanterns were used for the development of a six-step synthesis of benzimidazoles. A library of 3840 benzimidazoles was prepd. on Mimotope's double lanterns using the sort-and-combine strategy. A no. of micromolar agonists of Nurr1, which increased the luciferase reporter-gene activity by a factor of 2, could be identified by screening the first generation library of 3256 compds. To improve the potency of the first-generation hits, we designed and synthesized a second-generation library biased toward Nurr1. Very potent Nurrl agonists (e.g. I ) were thus rapidly identified by designing, synthesizing, and screening a first-generation library oriented toward nuclear receptors, followed by a small, biased second-generation library.
- 422Hintermann, S.; Chiesi, M.; von Krosigk, U.; Mathé, D.; Felber, R.; Hengerer, B. Identification of a Series of Highly Potent Activators of the Nurr1 Signaling Pathway. Bioorg. Med. Chem. Lett. 2007, 17 (1), 193– 196, DOI: 10.1016/j.bmcl.2006.09.062[Crossref], [PubMed], [CAS], Google Scholar426https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXislSg&md5=8cb547a0ff17183aaef9a87dd1db29efIdentification of a series of highly potent activators of the Nurr1 signaling pathwayHintermann, Samuel; Chiesi, Michele; von Krosigk, Ulrike; Mathe, Daniele; Felber, Richard; Hengerer, BastianBioorganic & Medicinal Chemistry Letters (2007), 17 (1), 193-196CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The nuclear receptor Nurr1 (NR4A2) is critically involved in the development and maintenance of midbrain dopaminergic neurons and is believed to function independently of endogenous activation. The hit identification and SAR studies leading to isoxazolo-pyridinone 7e (I), a highly potent, brain penetrable activator of the Nurr1 signaling pathway, are described.
- 423Li, X.; Lee, S.-O.; Safe, S. Structure-Dependent Activation of NR4A2 (Nurr1) by 1,1-Bis(3′- Indolyl)-1-(Aromatic)Methane Analogs in Pancreatic Cancer Cells. Biochem. Pharmacol. 2012, 83 (10), 1445– 1455, DOI: 10.1016/j.bcp.2012.02.021[Crossref], [PubMed], [CAS], Google Scholar427https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktFGitbY%253D&md5=c2a6e2dfb65f41fe9aa193af7335d25eStructure-dependent activation of NR4A2 (Nurr1) by 1,1-bis(3'-indolyl)-1-(aromatic)methane analogs in pancreatic cancer cellsLi, Xi; Lee, Syng-Ook; Safe, StephenBiochemical Pharmacology (2012), 83 (10), 1445-1455CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)NR4A2 (Nurr1) is an orphan nuclear receptor with no known endogenous ligands and is highly expressed in many cancer cell lines including Panc1 and Panc28 pancreatic cancer cells. Structure-dependent activation of NR4A2 by a series of 1,1-bis(3'-indolyl)-1-(arom.)methane (C-DIM) analogs was detd. in pancreatic cancer cells transfected with yeast GAL4-Nurr1 chimeras and a UASx5-luc reporter gene or constructs contg. response elements that bind NR4A2. Among 23 different structural analogs, Ph groups contg. p-substituted trifluoromethyl, t-Bu, cyano, bromo, iodo and trifluoromethoxy groups were the most active compds. in transactivation assay. The p-bromophenyl analog (DIM-C-pPhBr) was used as a model for structure-activity studies among a series of ortho-, meta- and para-bromophenyl isomers and the corresponding indole 2- and N-Me analogs. Results show that NR4A2 activation was maximal with the p-bromophenyl analog and methylation of the indole NH group abrogated activity. Moreover, using GAL4-Nurr1 (full length) or GAL-Nurr1-A/B and GAL4-Nurr1-(C-F) chimeras expressing N- and C-terminal domains of Nurr1, resp., DIM-C-pPhBr activated all three constructs and these responses were differentially affected by kinase inhibitors. DIM-C-pPhBr also modulated expression of several Nurr1-regulated genes in pancreatic cancer cells including vasoactive intestinal peptide (VIP), and the immunohistochem. and western blot analyses indicated that DIM-C-pPhBr activates nuclear NR4A2.
- 424Inamoto, T.; Papineni, S.; Chintharlapalli, S.; Cho, S. D.; Safe, S.; Kamat, A. M. 1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane Activates the Orphan Nuclear Receptor Nurr1 and Inhibits Bladder Cancer Growth. Mol. Cancer Ther. 2008, 7 (12), 3825– 3833, DOI: 10.1158/1535-7163.MCT-08-0730[Crossref], [PubMed], [CAS], Google Scholar428https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsV2iurbK&md5=1cfbb9b8327fcd644d5eb996b79e2e691,1-Bis(3'-indolyl)-1-(p-chlorophenyl)methane activates the orphan nuclear receptor Nurr1 and inhibits bladder cancer growthInamoto, Teruo; Papineni, Sabitha; Chintharlapalli, Sudhakar; Cho, Sung-Dae; Safe, Stephen; Kamat, Ashish M.Molecular Cancer Therapeutics (2008), 7 (12), 3825-3833CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Nurr1 is an orphan nuclear receptor and a member of the nerve growth factor I-B subfamily of transcription factors with no known endogenous ligand or stimulator. We show, for the first time, evidence that Nurr1 is expressed in a panel of 11 human bladder cancer cell lines. A new class of methylene-substituted diindolylmethanes (C-DIM) were screened and 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (DIM-C-pPhCl) activated the ligand-binding domain of Nurr1. Treatment of bladder cancer cells with Nurr1-active C-DIM resulted in decreased cell survival (MTT assay) and induction of cell death pathways, resulting in poly(ADP-ribose) polymerase cleavage and DNA fragmentation. The specificity of the Nurr1-active compd. was shown using RNA interference in 253J B-V cells, whereby small interfering RNA against Nurr1 attenuated ligand-dependent activation of Nurr1 and poly(ADP-ribose) polymerase cleavage. Furthermore, activation of Nurr1 resulted in stimulation of tumor necrosis factor-related apoptosis-inducing ligand and small interfering RNA expts. attenuated tumor necrosis factor-related apoptosis-inducing ligand prodn. In an orthotopic model of human bladder tumors established in nude mice, administration of a Nurr1-active C-DIM suppressed bladder cancer growth. These results identify Nurr1 as a potential target for bladder cancer therapy and also identify a novel agent for activating Nurr1.
- 425De Miranda, B. R.; Popichak, K. A.; Hammond, S. L.; Miller, J. A.; Safe, S.; Tjalkens, R. B. Novel Para-Phenyl Substituted Diindolylmethanes Protect against MPTP Neurotoxicity and Suppress Glial Activation in a Mouse Model of Parkinson’s Disease. Toxicol. Sci. 2015, 143 (2), 360– 373, DOI: 10.1093/toxsci/kfu236[Crossref], [PubMed], [CAS], Google Scholar429https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFGlt7c%253D&md5=338bb8a7a471bc88999ac934ee168fa0Novel para-phenyl substituted diindolylmethanes protect against MPTP neurotoxicity and suppress glial activation in a mouse model of Parkinson's diseaseDe Miranda, Briana R.; Popichak, Katriana A.; Hammond, Sean L.; Miller, James A.; Safe, Stephen; Tjalkens, Ronald B.Toxicological Sciences (2015), 143 (2), 360-373CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)The orphan nuclear receptor NR4A2 (Nurr1) constitutively regulates inflammatory gene expression in glial cells by suppressing DNA binding activity of NF-κB. We recently reported that novel 1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methane (C-DIM) compds. that activate NR4A family nuclear receptors in cancer lines also suppress inflammatory gene expression in primary astrocytes and prevent loss of dopaminergic neurons in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp). In this study, we postulated that the basis for this neuroprotection involves blockade of glial activation and subsequent expression of NF-κB-regulated inflammatory genes. To examine this mechanism, we treated transgenic NF-κB/EGFP reporter mice with MPTPp for 7 days (MPTPp7d) followed by daily oral gavage with either vehicle (corn oil; MPTPp14d) or C-DIMs contg. p-methoxyphenyl (C-DIM5), p-hydroxyphenyl (C-DIM8), or p-chlorophenyl (C-DIM12) groups. Each compd. conferred significant protection against progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), even when given after 7 days of dosing with MPTPp. C-DIM12 had the greatest neuroprotective activity in MPTPp-treated mice, and was also the most potent compd. in suppressing activation of microglia and astrocytes, expression of cytokines and chemokines in quant. polymerase chain reaction (qPCR) array studies, and in reducing expression of NF-κB/EGFP in the SN. C-DIM12 prevented nuclear export of Nurr1 in dopaminergic neurons and enhanced expression of the Nurr1-regulated proteins tyrosine hydroxylase and the dopamine transporter. These data indicate that NR4A-active C-DIM compds. protect against loss of dopamine neurons in the MPTPp model of PD by preventing glial-mediated neuronal injury and by supporting a dopaminergic phenotype in TH-pos. neurons in the SNpc.
- 426Hammond, S. L.; Safe, S.; Tjalkens, R. B. A Novel Synthetic Activator of Nurr1 Induces Dopaminergic Gene Expression and Protects against 6-Hydroxydopamine Neurotoxicity in Vitro. Neurosci. Lett. 2015, 607, 83– 89, DOI: 10.1016/j.neulet.2015.09.015[Crossref], [PubMed], [CAS], Google Scholar430https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1SlurnJ&md5=0d9a83edeeec515918023b330ab72f50A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitroHammond, Sean L.; Safe, Stephen; Tjalkens, Ronald B.Neuroscience Letters (2015), 607 (), 83-89CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Degeneration of dopaminergic neurons in Parkinson's disease (PD) is assocd. with decreased expression of the orphan nuclear receptor Nurr1 (NR4A2), which is crit. for both homeostasis and development of dopamine (DA) neurons. The synthetic, phytochem.-based compd., 1,1-bis (3'-indolyl)-1-(p-chlorophenyl) methane (C-DIM12) activates Nurr1 in cancer cells and prevents loss of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice. In the present study, we examd. the capacity of C-DIM12 to induce expression of Nurr1-regulated genes in two dopaminergic neuronal cell lines (N2A, N27) and to protect against 6-hydroxydopamine (6-OHDA) neurotoxicity. C-DIM12 induced expression of Nurr1-regulated genes that was abolished by Nurr1 knockdown. C-DIM12 increased expression of transfected human Nurr1, induced Nurr1 protein expression in primary dopaminergic neurons and enhanced neuronal survival from exposure to 6-OHDA. These data indicate that C-DIM12 stimulates neuroprotective expression Nurr1-regulated genes in DA neurons.
- 427Hammond, S. L.; Tjalkens, R. B.; Safe, S.; Richman, E. H.; Backos, D. S.; Li, X.; Hunt, L. G.; Chong, E.; Popichak, K. A.; Damale, P. The Nurr1 Ligand,1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism. J. Pharmacol. Exp. Ther. 2018, 365 (3), 636– 651, DOI: 10.1124/jpet.117.246389[Crossref], [PubMed], [CAS], Google Scholar431https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVCntb3O&md5=77dd95db62e674cd310b56a041be2b89The Nurr1 ligand,1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane, modulates glial reactivity and is neuroprotective in MPTP-induced parkinsonismsHammond, Sean L.; Popichak, Katriana A.; Li, Xi; Hunt, Lindsay G.; Richman, Evan H.; Damale, Pranav U.; Chong, Edwin K. P.; Backos, Donald S.; Safe, Stephen; Tjalkens, Ronald B.Journal of Pharmacology and Experimental Therapeutics (2018), 365 (3), 636-651CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)We postulated that the activation of Nurr1 would suppress the activation of glia and thereby protect against loss of DA neurons after subacute lesioning with MPTP. Our previous studies have shown that a synthetic Nurr1 ligand, C-DIM12, suppresses inflammatory gene expression in primary astrocytes and induces a dopaminergic phenotype in neurons. Pharmacokinetic anal. of C-DIM12 in mice by liq. chromatog.-mass spectrometry demonstrated that approx. three times more compd. concd. in the brain than in plasma. Mice treated with four doses of MPTP + probenecid over 14 days were monitored for neurobehavioral function, loss of dopaminergic neurons, and glial activation. C-DIM12 protected against the loss of DA neurons in the substantia nigra pars compacta and DA terminals in the striatum, maintained a ramified phenotype in microglia, and suppressed activation of astrocytes. In vitro reporter assays demonstrated that C-DIM12 was an effective activator of Nurr1 transcription in neuronal cell lines. Computational modeling of C-DIM12 binding to the three-dimensional structure of human Nurr1 identified a high-affinity binding interaction with Nurr1 at the coactivator domain. Taken together, these data suggest that C-DIM12 is an activator of Nurr1 that suppresses glial activation and neuronal loss in vivo after treatment with MPTP, and that this receptor could be an efficacious target for disease modification in individuals with Parkinson's disease and related disorders.
- 428Karki, K.; Li, X.; Jin, U.-H.; Mohankumar, K.; Zarei, M.; Michelhaugh, S. K.; Mittal, S.; Tjalkens, R.; Safe, S. Nuclear Receptor 4A2 (NR4A2) Is a Druggable Target for Glioblastomas. J. Neuro-Oncol. 2020, 146 (1), 25– 39, DOI: 10.1007/s11060-019-03349-y[Crossref], [PubMed], [CAS], Google Scholar432https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlCitb7P&md5=c59faaf59f390c4f657c058a44ff8791Nuclear receptor 4A2 (NR4A2) is a druggable target for glioblastomasKarki, Keshav; Li, Xi; Jin, Un-Ho; Mohankumar, Kumaravel; Zarei, Mahsa; Michelhaugh, Sharon K.; Mittal, Sandeep; Tjalkens, Ronald; Safe, StephenJournal of Neuro-Oncology (2020), 146 (1), 25-39CODEN: JNODD2; ISSN:0167-594X. (Springer)Introduction: The orphan nuclear receptor 4A2 (NR4A2) has been extensively characterized in subcellular regions of the brain and is necessary for the function of dopaminergic neurons. The NR4A2 ligand, 1,1-bis (31-indoly1)-1-(p-chlorophenyl)methane (DIM-C-pPhCl) inhibits markers of neuroinflammation and degeneration in mouse models and in this study we investigated expression and function of NR4A2 in glioblastoma (GBM). Established and patient-derived cell lines were used as models and the expression and functions of NR4A2 were detd. by western blots and NR4A2 gene silencing by antisense oligonucleotides resp. Effects of NR4A2 knockdown and DIM-C-pPhCl on cell growth, induction of apoptosis (Annexin V Staining) and migration/invasion (Boyden chamber and spheroid invasion assay) and transactivation of NR4A2-regulated reporter genes were detd. Tumor growth was investigated in athymic nude mice bearing U87-MG cells as xenografts. NR4A2 knockdown and DIM-C-pPhCl inhibited GBM cell and tumor growth, induced apoptosis and inhibited migration and invasion of GBM cells. DIM-C-pPhCl and related analogs also inhibited NR4A2-regulated transactivation (luciferase activity) confirming that DIM-C-pPhCl acts as an NR4A2 antagonist and blocks NR4A2-dependent pro-oncogenic responses in GBM. Conclusion: We demonstrate for the first time that NR4A2 is pro-oncogenic in GBM and thus a potential druggable target for patients with tumors expressing this receptor. Moreover, our bis-indole-derived NR4A2 antagonists represent a novel class of anti-cancer agents with potential future clin. applications for treating GBM.
- 429De Miranda, B. R.; Miller, J. A.; Hansen, R. J.; Lunghofer, P. J.; Safe, S.; Gustafson, D. L.; Colagiovanni, D.; Tjalkens, R. B. Neuroprotective Efficacy and Pharmacokinetic Behavior of Novel Anti-Inflammatory Para-Phenyl Substituted Diindolylmethanes in a Mouse Mdel of Parkinson’s Disease. J. Pharmacol. Exp. Ther. 2013, 345 (1), 125– 138, DOI: 10.1124/jpet.112.201558[Crossref], [PubMed], [CAS], Google Scholar433https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlsVyrs7c%253D&md5=35f561028811c12226919fd1bc44adafNeuroprotective efficacy and pharmacokinetic behavior of novel anti-inflammatory para-phenyl substituted diindolylmethanes in a mouse model of Parkinson's diseaseDe Miranda, Briana R.; Miller, James A.; Hansen, Ryan J.; Lunghofer, Paul J.; Safe, Stephen; Gustafson, Daniel L.; Colagiovanni, Dorothy; Tjalkens, Ronald B.Journal of Pharmacology and Experimental Therapeutics (2013), 345 (1), 125-138CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)There are currently no registered drugs that slow the progression of neurodegenerative diseases, in part because translation from animal models to the clinic has been hampered by poor distribution to the brain. The present studies examd. a selected series of para-phenyl-substituted diindolylmethane (C-DIM) compds. that display anti-inflammatory and neuroprotective efficacy in vitro. We postulated that the pharmacokinetic behavior of C-DIM compds. after oral administration would correlate with neuroprotective efficacy in vivo in a mouse model of Parkinson's disease. Pharmacokinetics and metab. of 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (C-DIM5), 1,1-bis(3'-indolyl)-1-(phenyl)methane, 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (C-DIM8), and 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) were detd. in plasma and brain of C57Bl/6 mice after oral and i.v. administration at 10 and 1 mg/Kg, resp. Putative metabolites were measured in plasma, liver, and urine. C-DIM compds. given orally displayed the highest area under the curve, Cmax, and Tmax levels, and C-DIM12 exhibited the most favorable pharmacokinetics of the compds. tested. Oral bioavailability of each compd. ranged from 6% (C-DIM8) to 42% (C-DIM12). After pharmacokinetic studies, the neuroprotective efficacy of C-DIM5, C-DIM8, and C-DIM12 (50 mg/Kg per oral) was examd. in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid for 14 days, a model of progressive neurodegeneration with a strong neuroinflammatory component. C-DIM5 and C-DIM12 given orally once daily after one week of exposure to MPTP and probenecid prevented further loss of dopaminergic neurons in the substantia nigra pars compacta and striatal dopamine terminals, indicating that these compds. could be effective therapeutic agents to prevent neurodegeneration.
- 430Hibino, S.; Chikuma, S.; Kondo, T.; Ito, M.; Nakatsukasa, H.; Omata-Mise, S.; Yoshimura, A. Inhibition of Nr4a Receptors Enhances Antitumor Immunity by Breaking Treg-Mediated Immune Tolerance. Cancer Res. 2018, 78 (11), 3027– 3040, DOI: 10.1158/0008-5472.CAN-17-3102[Crossref], [PubMed], [CAS], Google Scholar434https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVKjsb%252FK&md5=8121148b58f88e18a3eead1fe7c50522Inhibition of Nr4a receptors enhances antitumor immunity by breaking Treg-mediated immune toleranceHibino, Sana; Chikuma, Shunsuke; Kondo, Taisuke; Ito, Minako; Nakatsukasa, Hiroko; Omata-Mise, Setsuko; Yoshimura, AkihikoCancer Research (2018), 78 (11), 3027-3040CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Enhanced infiltration of regulatory T cells (Treg) into tumor tissue is detrimental to patients with cancer and is closely assocd. with poor prognosis as they create an immunosuppressive state that suppresses antitumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here, we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg genetic programs, contribute to Treg-mediated suppression of antitumor immunity in the tumor microenvironment. Mice lacking Nr4a1 and Nr4a2 genes specifically in Tregs showed resistance to tumor growth in transplantation models without exhibiting any severe systemic autoimmunity. The chemotherapeutic agent camptothecin and a common cyclooxygenase-2 inhibitor were found to inhibit transcriptional activity and induction of Nr4a factors, and they synergistically exerted antitumor effects. Genetic inactivation or pharmacol. inhibition of Nr4a factors unleashed effector activities of CD8+ cytotoxic T cells and evoked potent antitumor immune responses. These findings demonstrate that inactivation of Nr4a in Tregs breaks immune tolerance toward cancer, and pharmacol. modulation of Nr4a activity may be a novel cancer treatment strategy targeting the immunosuppressive tumor microenvironment.
- 431Komiya, T.; Yamamoto, S.; Roy, A.; McDonald, P.; Perez, R. P. Drug Screening to Target Nuclear Orphan Receptor NR4A2 for Cancer Therapeutics. Transl. Lung Cancer Res. 2017, 6 (5), 600– 610, DOI: 10.21037/tlcr.2017.07.02[Crossref], [PubMed], [CAS], Google Scholar435https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2htrvJ&md5=b00932577e658f7561d7ee820fc02eeeDrug screening to target nuclear orphan receptor NR4A2 for cancer therapeuticsKomiya, Takefumi; Yamamoto, Satomi; Roy, Anuradha; McDonald, Peter; Perez, Raymond P.Translational Lung Cancer Research (2017), 6 (5), 600-610CODEN: TLCRA9; ISSN:2226-4477. (Pioneer Bioscience Publishing Co.)Our previous study suggested NR4A2, a subfamily member of orphan nuclear receptors, is essential for survival of human cancer cells such as mucoepidermoid carcinoma (MEC). We conducted high throughput drug screening for NR4A2 inhibitors as a novel therapeutic modality. Pos. screening was performed using a luciferase reporter vector contg. NR4A2 binding sequence, and a CRE-reporter control vector was used to eliminate false positives. In vitro assays for pos. hits were conducted. A total of 23 Food and Drug Administration (FDA) and 43 Life Science Library compds. were identified, including several epidermal growth factor inhibitors and Src inhibitors. Subsequent in vitro assays confirmed that identified compds. were preferentially active in NR4A2+ cancer cells. Several candidate compds. appeared to suppress NR4A2 via inhibition of p-ERK, whereas a novel compd. KU0171309 may act as a more direct inhibitor. Further research should focus on homolog selectivity, in vivo activity, and definitively deciphering the mechanism of action of KU0171309.
- 432Pan, T.; Xie, W.; Jankovic, J.; Le, W. Biological Effects of Pramipexole on Dopaminergic Neuron-Associated Genes: Relevance to Neuroprotection. Neurosci. Lett. 2005, 377 (2), 106– 109, DOI: 10.1016/j.neulet.2004.11.080[Crossref], [PubMed], [CAS], Google Scholar436https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhvVCrs74%253D&md5=02be75fd630d4d3269573743eb7f0780Biological effects of pramipexole on dopaminergic neuron-associated genes: relevance to neuroprotectionPan, Tianhong; Xie, Wenjie; Jankovic, Joseph; Le, WeidongNeuroscience Letters (2005), 377 (2), 106-109CODEN: NELED5; ISSN:0304-3940. (Elsevier Ltd.)Pramipexole (PRX) is a nonergot dopamine (DA) D2/D3 receptor agonist. Exptl. studies have provided evidence that PRX may exert neuroprotective effects on the nigro-striatal system. Recent studies have demonstrated a slower decline of DAT d. in Parkinson's disease patients treated with PRX as measured by SPECT. The aim of this study is to det. whether PRX has direct biol. effects on DAergic neuron-assocd. genes expression, including DAT, VMAT2, and Nurr1. The human neuroblastoma SH-SY5Y cells were treated with PRX for various time periods and harvested to measure the mRNA and protein products of these genes. Treatment with PRX at 10 μM significantly increased DAT mRNA levels by 54-130% in 4-8 h, VMAT2 mRNA levels by 34% in 4 h, and Nurr1 mRNA levels by 31-39% in 2-4 h, which was the earliest induction among these three genes. The protein levels of DAT, VMAT2, and Nurr1 were markedly increased after PRX treatment, among which the increase of Nurr1 protein level was the highest at first 2 h treatment of PRX. Nafadotride, a D3 DA receptor antagonist, blocked the increase of Nurr1 gene expression induced by PRX, while eticlopride, a D2 DA receptor antagonist, did not show this effect. The findings that PRX has biol. regulatory effects on DAergic neuron-assocd. genes may explain both the slower decline of imaged DAT and the neuroprotective effect of PRX. Furthermore, our results suggest that the induction of Nurr1 gene expression by PRX may be mediated by D3 DA receptor.
- 433Hedya, S. A.; Safar, M. M.; Bahgat, A. K. Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD Model. Mol. Neurobiol. 2018, 55 (9), 7579– 7587, DOI: 10.1007/s12035-018-0923-1[Crossref], [PubMed], [CAS], Google Scholar437https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXis1aktrc%253D&md5=0819fa052b325f29fbbecf5237007c78Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD ModelHedya, Shireen A.; Safar, Marwa M.; Bahgat, Ashraf K.Molecular Neurobiology (2018), 55 (9), 7579-7587CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Nuclear receptor related 1 (Nurr1) orphan receptor has emerged as a promising contender in ameliorating Parkinson's disease; thus, finding a suitable activator of Nurr1 receptor is an attracting target for treating PD. Cilostazol, a phosphodiesterase-3 inhibitor, recently showed a favorable neuroprotective activity in multiple devastating central disorders, yet the possible antiparkinsonian activity of the drug has not been fully elucidated. Thus, the aim of this study is to explore the neuroprotective effect of cilostazol in rotenone-induced PD model in rats. Cilostazol successfully upregulated Nurr1 expression in PD rats, which resulted in successful preservation of the dopaminergic neuron functionality and integrity as verified by the marked improvement of motor performance in rotarod and open field tests, as well as the increased striatal tyrosine hydroxylase content. Moreover, cilostazol revealed an anti-inflammatory activity as manifested by hampering the global controller of inflammatory signaling pathway, nuclear factor-kappa B, together with its downstream pro-inflammatory cytokines, namely tumor necrosis factor-alpha and interleukin-1 beta, via Nurr-1 upregulation and glycogen synthase kinase 3 beta GSK-3β inhibition. In turn, the increase in GSK-3β inhibited form suppressed the measured downstream apoptotic biomarkers, viz. cytochrome C and caspase-3. Remarkably, cilostazol enhanced autophagy as depicted by hampering both LC3-II and P62 levels possibly through the prominent rise in sirtuin 1 level. In conclusion, cilostazol could be a promising candidate for PD treatment through modulating Nurr1 expression, as well as SIRT-1/autophagy, and GSK-3β/apoptosis cross-regulation. [Figure not available: see fulltext.].
- 434Ham, A.; Lee, H. J.; Hong, S. S.; Lee, D.; Mar, W. Moracenin D from Mori Cortex Radicis Protects SH-SY5Y Cells against Dopamine-Induced Cell Death by Regulating Nurr1 and α-Synuclein Expression. Phytother. Res. 2012, 26 (4), 620– 624, DOI: 10.1002/ptr.3592[Crossref], [PubMed], [CAS], Google Scholar438https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xlt1artrw%253D&md5=8960a11e5614b814b3c8f0ed02011863Moracenin D from Mori Cortex Radicis Protects SH-SY5Y Cells against Dopamine-induced Cell Death by Regulating Nurr1 and α-Synuclein ExpressionHam, Ahrom; Lee, Hak Ju; Hong, Seong Su; Lee, Dongho; Mar, WoongchonPhytotherapy Research (2012), 26 (4), 620-624CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)In our efforts to find neuroprotective materials of plant origin, several compds. were isolated from Mori Cortex Radicis. The protective effect against dopamine-induced cell death was examd., and the subsequent effects on the levels of expression of Parkinson's disease-assocd. nurr1 and α-synuclein were evaluated in a dopamine-induced system. Five compds. were isolated and moracenin D protected cell death against dopamine-induction in human neuroblastoma SH-SY5Y cells. The effects of moracenin D on the levels of mRNA and protein expression of nurr1 and α-synuclein were subsequently examd. using reverse transcription-polymerase chain reaction (RT-PCR) and western blot anal. Treatment with moracenin D resulted in an up-regulation of nurr1 mRNA levels and a down-regulation of α-synuclein mRNA levels. Addnl., the α-synuclein protein expression was decreased in accordance with an increase in nurr1 protein expression. These results demonstrate that the protective effects of moracenin D were presumably due to the correlative effects on the up-regulation of nurr1 and down-regulation of α-synuclein expressions against dopamine induction. Therefore, moracenin D can be considered as a candidate for therapy for Parkinson's disease. Copyright © 2011 John Wiley & Sons, Ltd.
- 435Wallén-Mackenzie, Å.; De Urquiza, A. M.; Petersson, S.; Rodriguez, F. J.; Friling, S.; Wagner, J.; Ordentlich, P.; Lengqvist, J.; Heyman, R. A.; Arenas, E.; Perlmann, T. Nurr1-RXR Heterodimers Mediate RXR Ligand-Induced Signaling in Neuronal Cells. Genes Dev. 2003, 17 (24), 3036– 3047, DOI: 10.1101/gad.276003[Crossref], [PubMed], [CAS], Google Scholar439https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhs1Shtg%253D%253D&md5=775b3bea209013c2a9c5f616a26ecd9dNurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cellsWallen-Mackenzie, Asa; Mata de Urquiza, Alexander; Petersson, Susanna; Rodriguez, Francisco J.; Friling, Stina; Wagner, Joseph; Ordentlich, Peter; Lengqvist, Johan; Heyman, Richard A.; Arenas, Ernest; Perlmann, ThomasGenes & Development (2003), 17 (24), 3036-3047CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)The retinoid X receptor (RXR) is essential as a common heterodimerization partner of several nuclear receptors (NRs). However, its function as a bona fide receptor for endogenous ligands has remained poorly understood. Such a role would depend on the existence of RXR activating ligands in vivo and on the ability of such ligands to influence relevant biol. functions. Here we demonstrate the presence of endogenous RXR ligands in the embryonic central nervous system (CNS) and show that they can activate heterodimers formed between RXR and the orphan NR Nurr1 in vivo. Moreover, RXR ligands increase the no. of surviving dopaminergic cells and other neurons in a process mediated by Nurr1-RXR heterodimers. These results provide evidence for a role of Nurr1 as a ligand-independent partner of RXR in its function as a bona fide ligand-activated NR. Finally, our findings identify RXR-Nurr1 heterodimers as a potential target in the treatment of neurodegenerative disease.
- 436Morita, K.; Kawana, K.; Sodeyama, M.; Shimomura, I.; Kagechika, H.; Makishima, M. Selective Allosteric Ligand Activation of the Retinoid X Receptor Heterodimers of NGFI-B and Nurr1. Biochem. Pharmacol. 2005, 71 (1–2), 98– 107, DOI: 10.1016/j.bcp.2005.10.017[Crossref], [PubMed], [CAS], Google Scholar440https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1OlsLrM&md5=8364846e8af567e47a35eacaa8c1dbd2Selective allosteric ligand activation of the retinoid X receptor heterodimers of NGFI-B and Nurr1Morita, Kentaro; Kawana, Katsuyoshi; Sodeyama, Mariko; Shimomura, Iichiro; Kagechika, Hiroyuki; Makishima, MakotoBiochemical Pharmacology (2005), 71 (1-2), 98-107CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)NGFI-B, an orphan member of the NR4A subfamily of the nuclear receptors, recognizes specific sequences in the promoters of neuronal target genes as a monomer. Although NGFI-B also forms a heterodimer with the retinoid X receptor (RXR), a receptor for 9-cis retinoic acid (9CRA), endogenous targets of the heterodimer have not been identified. We investigated the role of RXR ligand binding in NGFI-B/RXR activation and found that dibenzodiazepine-derived ligands, such as the weak RXR agonist HX600, selectively activate NGFI-B/RXR heterodimers. HX600 also activated the heterodimer formed by RXR and Nurr1, another NR4A subfamily receptor. In an assembly assay that detects ligand-dependent reconstruction of the ligand-binding domain, HX600 and not 9CRA induced an allosteric ligand effect on NGFI-B through RXRα binding. The data indicate that the RXR heterodimers of NGFI-B and Nurr1 are selectively activated by the RXR ligand HX600, and that compds. such as HX600 will be valuable tools in investigating NGFI-B and Nurr1 function.
- 437Ishizawa, M.; Kagechika, H.; Makishima, M. NR4A Nuclear Receptors Mediate Carnitine Palmitoyltransferase 1A Gene Expression by the Rexinoid HX600. Biochem. Biophys. Res. Commun. 2012, 418 (4), 780– 785, DOI: 10.1016/j.bbrc.2012.01.102[Crossref], [PubMed], [CAS], Google Scholar441https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitFyjtb8%253D&md5=630f2c03f912772d376790865252f01aNR4A nuclear receptors mediate carnitine palmitoyltransferase 1A gene expression by the rexinoid HX600Ishizawa, Michiyasu; Kagechika, Hiroyuki; Makishima, MakotoBiochemical and Biophysical Research Communications (2012), 418 (4), 780-785CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and can be activated by 9-cis retinoic acid (9CRA). RXRs form homodimers and heterodimers with other nuclear receptors such as the retinoic acid receptor and NR4 subfamily nuclear receptors, Nur77 and NURR1. Potential physiol. roles of the Nur77-RXR and NURR1-RXR heterodimers have not been elucidated. In this study, the authors identified a gene regulated by these heterodimers utilizing HX600, a selective RXR agonist for Nur77-RXR and NURR1-RXR. While 9CRA induced many genes, including RAR-target genes, HX600 effectively induced only carnitine palmitoyltransferase 1A (CPT1A) in human teratocarcinoma NT2/D1 cells, which express RXRα, Nur77 and NURR1. HX600 also increased CPT1A expression in human embryonic kidney (HEK) 293 cells and hepatocyte-derived HepG2 cells. Although HX600 induced CPT1A less effectively than 9CRA, overexpression of Nur77 or NURR1 increased the HX600 response to levels similar to 9CRA in NT2/D1 and HEK293 cells. A dominant-neg. form of Nur77 or NURR1 repressed the induction of CPT1A by HX600. A protein synthesis inhibitor did not alter HX600-dependent CPT1A induction. Thus, the rexinoid HX600 directly induces expression of CPT1A through a Nur77 or NURR1-mediated mechanism. CPT1A, a gene involved in fatty acid β-oxidn., could be a target of RXR-NR4 receptor heterodimers.
- 438Sundén, H.; Schäfer, A.; Scheepstra, M.; Leysen, S.; Malo, M.; Ma, J.-N.; Burstein, E. S.; Ottmann, C.; Brunsveld, L.; Olsson, R. Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation. J. Med. Chem. 2016, 59 (3), 1232– 1238, DOI: 10.1021/acs.jmedchem.5b01702[ACS Full Text], [CAS], Google Scholar442https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVWlsro%253D&md5=64a2afc980aa80962992640a486a5710Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer ActivationSunden, Henrik; Schaefer, Anja; Scheepstra, Marcel; Leysen, Seppe; Malo, Marcus; Ma, Jian-Nong; Burstein, Ethan S.; Ottmann, Christian; Brunsveld, Luc; Olsson, RogerJournal of Medicinal Chemistry (2016), 59 (3), 1232-1238CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist I at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where I optimally addresses the ligand binding pocket of RXR.
- 439Scheepstra, M.; Andrei, S. A.; de Vries, R. M. J. M.; Meijer, F. A.; Ma, J.-N.; Burstein, E. S.; Olsson, R.; Ottmann, C.; Milroy, L.-G.; Brunsveld, L. Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization. ACS Chem. Neurosci. 2017, 8 (9), 2065– 2077, DOI: 10.1021/acschemneuro.7b00216[ACS Full Text], [CAS], Google Scholar443https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCju7nP&md5=665fbd39142e946b3fdf097a345675f2Ligand Dependent Switch from RXR Homo- to RXR-NURR1 HeterodimerizationScheepstra, Marcel; Andrei, Sebastian A.; de Vries, Rens M. J. M.; Meijer, Femke A.; Ma, Jian-Nong; Burstein, Ethan S.; Olsson, Roger; Ottmann, Christian; Milroy, Lech-Gustav; Brunsveld, LucACS Chemical Neuroscience (2017), 8 (9), 2065-2077CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Retinoid X Receptors (RXRs) play key roles in many physiol. processes in both the periphery and central nervous system. In addn., RXRs form heterodimers with other nuclear receptors to exert their physiol. effects. The Nuclear Receptor Related 1 protein (NURR1) is particularly interesting because of its role in promoting differentiation and survival of dopamine neurons. However only a small no. of RXR-heterodimer selective modulators are available, with limited chem. diversity. This work describes the synthesis, biochem. evaluation and structural elucidation of a novel series of RXR ligands with strongly biased interactions with RXRα-NURR1 heterodimers. Targeted modifications to the small mol. biaryl scaffold caused local RXRα side-chain disturbances and displacement of secondary structural elements upon ligand binding. This resulted in the repositioning of protein helixes in the heterodimer interface of RXRα, alterations in homo- vs. heterodimer formation, and modulation of activation function 2 (AF2). The data provide a rationale for the design of RXR ligands consisting of a highly conserved hydrophilic region, strongly contributing to the ligand affinity, and a variable hydrophobic region, which efficiently probes the effects of structural changes at the level of the ligand on co-regulator recruitment or the RXRα-NURR1 dimerization interface.
- 440McFarland, K.; Spalding, T. A.; Hubbard, D.; Ma, J.-N.; Olsson, R.; Burstein, E. S. Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson’s Disease. ACS Chem. Neurosci. 2013, 4 (11), 1430– 1438, DOI: 10.1021/cn400100f[ACS Full Text], [CAS], Google Scholar444https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1SgsLrN&md5=54d129a78f986304f82ea3f723202129Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson's DiseaseMcFarland, Krista; Spalding, Tracy A.; Hubbard, David; Ma, Jian-Nong; Olsson, Roger; Burstein, Ethan S.ACS Chemical Neuroscience (2013), 4 (11), 1430-1438CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Nurr1 is a nuclear hormone receptor (NucHR) strongly implicated in the growth, maintenance, and survival of dopaminergic neurons. Nurr1 may be unable to bind ligands directly, but it forms heterodimers with other NucHRs that do. Using bioluminescence resonance energy transfer (BRET) assays to directly monitor interactions of Nurr1 with other NucHRs, we found the cancer drug bexarotene (Targretin, also LGD1069) displayed biased interactions with Nurr1-RXR heterodimers compared with RXR-RXR homodimers. Remarkably, at doses up to 100-fold lower than those effective in rodent cancer models, bexarotene rescued dopamine neurons and reversed behavioral deficits in 6-hydroxydopamine (6-OHDA) lesioned rats. Compared to the high doses used in cancer therapy, low doses of bexarotene have significantly milder side effects including a reduced increase in plasma triglycerides and less suppression of thyroid function. On the basis of extrapolations from rat to human doses, we hypothesize that low oral doses of bexarotene may provide an effective and tolerated therapy for Parkinson's disease (PD).
- 441Pönniö, T.; Conneely, O. M. Nor-1 Regulates Hippocampal Axon Guidance, Pyramidal Cell Survival, and Seizure Susceptibility. Mol. Cell. Biol. 2004, 24 (20), 9070– 9078, DOI: 10.1128/MCB.24.20.9070-9078.2004[Crossref], [PubMed], [CAS], Google Scholar445https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cvovVKqsg%253D%253D&md5=101cd310a3e866ffcc7acf8f7597f495nor-1 regulates hippocampal axon guidance, pyramidal cell survival, and seizure susceptibilityPonnio Tiia; Conneely Orla MMolecular and cellular biology (2004), 24 (20), 9070-8 ISSN:0270-7306.The nuclear receptor transcription factor, nor-1, is expressed during mammalian development predominantly in the nervous system and is induced in a cell-specific manner in nonneuronal cells in response to a variety of extracellular stimuli. To elucidate the essential developmental functions of this transcription factor, we have analyzed the consequences of its elimination on central nervous system development in mice. Here we show that null mutant mice lacking nor-1 respond with increased limbic seizure activity to the excitotoxic glutamate receptor agonist kainic acid. We demonstrate that these abnormalities are associated with defective postnatal hippocampal development exemplified by abnormal axonal guidance of dentate gyrus granule and mossy cells, disorganization of the pyramidal cell layer, and early postnatal death of pyramidal neurons in the CA1 field of the hippocampus. Our data indicate that nor-1 plays a critical role in neuronal survival and axonal guidance in the developing murine hippocampus and that hippocampal dysgenesis in nor-1-/- mice may be an underlying cause of seizure susceptibility.
- 442Ferrán, B.; Martí-Pàmies, I.; Alonso, J.; Rodríguez-calvo, R.; Aguiló, S.; Vidal, F.; Rodríguez, C.; Martínez-gonzález, J. The Nuclear Receptor NOR-1 Regulates the Small Muscle Protein, X-Linked (SMPX) and Myotube Differentiation. Sci. Rep. 2016, 6, 25944, DOI: 10.1038/srep25944[Crossref], [PubMed], [CAS], Google Scholar446https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XotFOjsr8%253D&md5=eeb6a3bd40da22f70e570f575593ee07The nuclear receptor NOR-1 regulates the small muscle protein, X-linked (SMPX) and myotube differentiationFerran, Beatriz; Marti-Pamies, Ingrid; Alonso, Judith; Rodriguez-Calvo, Ricardo; Aguilo, Silvia; Vidal, Francisco; Rodriguez, Cristina; Martinez-Gonzalez, JoseScientific Reports (2016), 6 (), 25944CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Recent works have highlighted the role of NOR-1 in both smooth and skeletal muscle, and have proposed this nuclear receptor as a nexus that coordinates muscle performance and metabolic capacity. However, no muscle specific genes regulated by NOR-1 have been identified so far. To identify NOR-1 target genes, we over-expressed NOR-1 in human vascular smooth muscle cells (VSMC). These cells subjected to sustained over-expression of supraphysiol. levels of NOR-1 experienced marked phenotypic changes and up-regulated the skeletal muscle protein X-linked (SMPX), a protein typically expressed in striated muscle and assocd. to cell shape. By transcriptional studies and DNA-protein binding assays, we identified a non-consensus NBRE site in human SMPX promoter, crit. for NOR-1 responsiveness. The expression of SMPX was higher in human skeletal muscle myoblasts (HSMM) than in human VSMC, and further increased in HSMM differentiated to myotubes. NOR-1 silencing prevented SMPX expression in HSMM, as well as their differentiation to myotubes, but the up-regulation of SMPX was dispensable for HSMM differentiation. Our results indicate that NOR-1 regulate SMPX in human muscle cells and acts as a muscle regulatory factor, but further studies are required to unravel its role in muscle differentiation and hypertrophy.
- 443Kon, T.; Miki, Y.; Tanji, K.; Mori, F.; Tomiyama, M.; Toyoshima, Y.; Kakita, A.; Takahashi, H.; Utsumi, J.; Sasaki, H.; Wakabayashi, K. Localization of Nuclear Receptor Subfamily 4, Group A, Member 3 (NR4A3) in Lewy Body Disease and Multiple System Atrophy. Neuropathology 2015, 35 (6), 503– 509, DOI: 10.1111/neup.12210[Crossref], [PubMed], [CAS], Google Scholar447https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFKrurnO&md5=e3185f1e84fdfefb9c5e610839545e21Localization of nuclear receptor subfamily 4, group A, member 3 (NR4A3) in Lewy body disease and multiple system atrophyKon, Tomoya; Miki, Yasuo; Tanji, Kunikazu; Mori, Fumiaki; Tomiyama, Masahiko; Toyoshima, Yasuko; Kakita, Akiyoshi; Takahashi, Hitoshi; Utsumi, Jun; Sasaki, Hidenao; Wakabayashi, KoichiNeuropathology (2015), 35 (6), 503-509CODEN: NOPAFH; ISSN:1440-1789. (John Wiley & Sons, Inc.)Nuclear receptor subfamily 4, group A, member 3 (NR4A3), also known as neuron-derived orphan receptor-1, is a nuclear receptor which plays key roles in cell cycle, neuronal differentiation, apoptosis and metab. These processes may be involved in the pathogenesis of certain neurodegenerative diseases. Previous studies have shown that there are high levels of NR4A3 mRNA in the CNS. Moreover, NR4A2, a transcription factor with homol. to NR4A3, has been reported to contribute to the pathogenesis of Parkinson's disease. However, it is uncertain whether NR4A3 is also involved in diseases such as dementia with Lewy bodies, multiple system atrophy, and other neurodegenerative disorders such as tauopathies, TDP-43 proteinopathies and polyglutamine diseases. In the present study we used immunohistochem. to examine the brain and spinal cord from patients with various neurodegenerative diseases and normal control subjects using two polyclonal anti-NR4A3 antibodies. In controls, the cytoplasm of neurons and glial cells was faintly immunostained with anti-NR4A3 antibodies. In tissues from patients with neurodegenerative diseases, immunoreactivity for NR4A3 was obsd. in cortical and brainstem-type Lewy bodies in Parkinson's disease and in dementia with Lewy bodies, as well as in neuronal and glial cytoplasmic inclusions in multiple system atrophy. A double-labeled immunofluorescence study showed co-localization of NR4A3 and phosphorylated α-synuclein in these inclusions. Neuronal and glial inclusions in other neurodegenerative disorders were NR4A3 neg. These findings suggest that accumulation of NR4A3 is specific to α-synucleinopathy.
- 444Maheux, J.; Ethier, I.; Rouillard, C.; Levesque, D. Induction Patterns of Transcription Factors of the Nur Family (Nurr1, Nur77, and Nor −1) by Typical and Atypical Antipsychotics in the Mouse Brain : Implication for Their Mechanism of Action. J. Pharmacol. Exp. Ther. 2005, 313 (1), 460– 473, DOI: 10.1124/jpet.104.080184[Crossref], [PubMed], [CAS], Google Scholar448https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjtlSnt7g%253D&md5=8442134083ae68da2a546c90c9fc70ecInduction patterns of transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) by typical and atypical antipsychotics in the mouse brain: Implication for their mechanism of actionMaheux, Jerome; Ethier, Isabelle; Rouillard, Claude; Levesque, DanielJournal of Pharmacology and Experimental Therapeutics (2005), 313 (1), 460-473CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Monitoring gene expression has been intensively used to identify neurobiol. and neuroanatomical substrates assocd. with administration of antipsychotic drugs. Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors that have been recently assocd. with dopamine neurotransmission. Nurr1 is involved in midbrain dopamine neuron development. Nur77 and Nor-1 are expressed in dopaminoceptive areas such as the striatum, nucleus accumbens, and prefrontal cortex. To better understand the relationship between Nur and antipsychotic drug effects, we conducted a comprehensive evaluation of the effect of various typical and atypical antipsychotic drugs on the modulation of Nur mRNA levels. We show that differential patterns of Nur expression can be obtained with typical and atypical antipsychotic drugs. Modulation of Nur77 and Nor-1 mRNA expression by antipsychotics can be used to calc. an index that is predictive of the typical or atypical profile of antipsychotic drugs. Inductions of Nur by antipsychotic drugs are correlated with dopamine D2 receptor in the striatum and D2 and D3 receptor subtypes in the nucleus accumbens. The 5-hydroxytryptamine2A/D2 affinity ratio of antipsychotics can also predict these patterns of inductions. In addn. to classical gene patterns induced in the striatal complex (striatum, accumbens) and cortex, most antipsychotic drugs tested strongly induced Nur77, Nor-1, and increased Nurr1 mRNA levels in the substantia nigra and ventral tegmental area. These data suggest that typical and atypical antipsychotic drugs might induce in multiple brain regions distinct Nur-dependent transcriptional activities, which may contribute to their pharmacol. effects.
- 445DeYoung, R. A.; Baker, J. C.; Cado, D.; Winoto, A. The Orphan Steroid Receptor Nur77 Family Member Nor-1 Is Essential for Early Mouse Embryogenesis. J. Biol. Chem. 2003, 278 (47), 47104– 47109, DOI: 10.1074/jbc.M307496200[Crossref], [PubMed], [CAS], Google Scholar449https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXovFKktL4%253D&md5=a379cbc1e20a0637a782e7bb55107c42The orphan steroid receptor Nur77 family member Nor-1 is essential for early mouse embryogenesisDeYoung, R. Andrea; Baker, Julie C.; Cado, Dragana; Winoto, AstarJournal of Biological Chemistry (2003), 278 (47), 47104-47109CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Nur77 and its family members, Nor-1 and Nurr1, are orphan steroid receptors implicated in a wide variety of biol. processes, including apoptosis and dopamine neuron agenesis. Expression of these family members can be detected at low levels in many tissues but they are expressed at very high levels when cells are stimulated by outside signals, including serum, nerve growth factor, and receptor engagement. Introduction of a dominant neg. Nur77 protein that blocks the activities of all family members led to inhibition of apoptosis in T cells. Nur77-deficient mice, however, exhibit no phenotype, and a line of Nor-1 mutant mice was reported to exhibit a mild ear development phenotype but no other gross abnormalities. Here, we report the generation of Nor-1-deficient mice with a block in early embryonic development. Nor-1 is expressed early during embryogenesis, and its loss leads to embryonic lethality around embryonic day 8.5 of gestation. The mutant embryos fail to complete gastrulation and display distinct morphol. abnormalities, including a decrease in overall size, developmental delay and an accumulation of mesoderm in the primitive streak during gastrulation. Abnormal expression of a no. of early developmental markers and defects in growth or distribution of emerging mesoderm cells were also detected. These data suggest that Nor-1 plays a crucial role in gastrulation.
- 446Chio, C.-C.; Wei, L.; Chen, T. G.; Lin, C.-M.; Shieh, J.-P.; Yeh, P.-S.; Chen, R.-M. Neuron-Derived Orphan Receptor 1 Transduces Survival Signals in Neuronal Cells in Response to Hypoxia-Induced Apoptotic Insults. J. Neurosurg. 2016, 124 (6), 1654– 1664, DOI: 10.3171/2015.6.JNS1535[Crossref], [PubMed], [CAS], Google Scholar451https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1Chsb3L&md5=333f467992ebd27714f3595884ea122fNeuron-derived orphan receptor 1 transduces survival signals in neuronal cells in response to hypoxia-induced apoptotic insultsChio, Chung-Ching; Wei, Li; Chen, Tyng Guey; Lin, Chien-Min; Shieh, Ja-Ping; Yeh, Poh-Shiow; Chen, Ruei-MingJournal of Neurosurgery (2016), 124 (6), 1654-1664CODEN: JONSAC; ISSN:0022-3085. (American Association of Neurosurgeons)Objective Hypoxia can induce cell death or trigger adaptive mechanisms to guarantee cell survival. Neuron-derived orphan receptor 1 (NOR-1) works as an early-response protein in response to a variety of environmental stresses. In this study, the authors evaluated the roles of NOR-1 in hypoxia-induced neuronal insults. Methods Neuro-2a cells were exposed to oxygen/glucose deprivation (OGD). Cell viability, cell morphol., cas-pase-3 activity, DNA fragmentation, and cell apoptosis were assayed to det. the mechanisms of OGD-induced neuronal insults. RNA and protein analyses were carried out to evaluate the effects of OGD on expressions of NOR-1, cAMP response element-binding (CREB), and cellular inhibitor of apoptosis protein 2 (cIAP2) genes. Translations of these gene expressions were knocked down using RNA interference. Mice subjected to traumatic brain injury (TBI) and NOR-1 was immunodetected. Results Exposure of neuro-2a cells to OGD decreased cell viability in a time-dependent manner. Addnl., OGD led to cell shrinkage, DNA fragmentation, and cell apoptosis. In parallel, treatment of neuro-2a cells with OGD time dependently increased cellular NOR-1 mRNA and protein expressions. Interestingly, administration of TBI also augmented NOR-1 levels in the impacted regions of mice. As to the mechanism, exposure to OGD increased nuclear levels of the transcription factor CREB protein. Downregulating CREB expression using RNA interference simultaneously inhibited OGD-induced NOR-1 mRNA expression. Also, levels of cIAP2 mRNA and protein in neuro-2a cells were augmented by OGD. After reducing cIAP2 translation, OGD-induced cell death was reduced. Sequentially, application of NOR-1 small interfering RNA to neuro-2a cells significantly inhibited OGD-induced cIAP2 mRNA expression and concurrently alleviated hypoxia-induced alterations in cell viability, caspase-3 activation, DNA damage, and cell apoptosis. Conclusions This study shows that NOR-1 can transduce survival signals in neuronal cells responsible for hypoxia-induced apoptotic insults through activation of a CREB/cIAP2-dependent mechanism.
- 447Kagaya, S.; Ohkura, N.; Tsukada, T.; Miyagawa, M.; Sugita, Y.; Tsujimoto, G.; Matsumoto, K.; Saito, H.; Hashida, R. Prostaglandin A 2 Acts as a Transactivator for NOR1 (NR4A3) within the Nuclear Receptor Superfamily. Biol. Pharm. Bull. 2005, 28 (9), 1603– 1607, DOI: 10.1248/bpb.28.1603[Crossref], [PubMed], [CAS], Google Scholar452https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFWjur3N&md5=ce8958564731cc5897bf6bb265f3d664Prostaglandin A2 acts as a transactivator for NOR1 (NR4A3) within the nuclear receptor superfamilyKagaya, Shinji; Ohkura, Naganari; Tsukada, Toshihiko; Miyagawa, Masami; Sugita, Yuji; Tsujimoto, Gozoh; Matsumoto, Kenji; Saito, Hirohisa; Hashida, RyoichiBiological & Pharmaceutical Bulletin (2005), 28 (9), 1603-1607CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)Within the nuclear receptor superfamily, Nur77, Nurr1, and NOR1 constitute the nuclear receptor subfamily 4 group A. Modulation of NOR1 function would be therapeutic potential for diseases related to dysfunction of NOR1, including extraskeletal myxoid chondrosarcoma and autoimmune diseases. By screening arachidonate metabolites for their capacity of transcriptional activation, we have identified prostaglandin (PG) A2 as a transactivator for NOR1. PGA2 acted as a potent activator of NOR1-dependent transcription through the GAL4-based reporter system. The putative ligand-binding domain (LBD) of the receptor directly bound PGA2, and LBD-deleted receptor showed little transcriptional activation by PGA2. Primary cultured spleen cells derived from transgenic mice overexpressing NOR1, showed higher sensitivity to PGA2 compared to those from wild-type mice. These observations suggest that PGA2 can serve as a transactivator of NOR1, and thus suggest a possibility of pharmacol. modulation of the NOR1 pathways by PGA2-related compds.
- 448Eyster, K. M. The Estrogen Receptors: An Overview from Different Perspectives. In Methods in Molecular Biology; Humana Press Inc., 2016; Vol. 1366, pp 1– 10.
- 449Dahlman-Wright, K.; Cavailles, V.; Fuqua, S. A.; Jordan, V. C.; Katzenellenbogen, J. A.; Korach, K. S.; Maggi, A.; Muramatsu, M.; Parker, M. G.; Gustafsson, J.-Å. International Union of Pharmacology. LXIV. Estrogen Receptors. Pharmacol. Rev. 2006, 58 (4), 773– 781, DOI: 10.1124/pr.58.4.8[Crossref], [PubMed], [CAS], Google Scholar456https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1aisA%253D%253D&md5=bf6fbc877371c6611a2ba612f11d05f0International union of pharmacology. LXIV. Estrogen receptorsDahlman-Wright, Karin; Cavailles, Vincent; Fuqua, Suzanne A.; Jordan, V. Craig; Katzenellenbogen, John A.; Korach, Kenneth S.; Maggi, Adriana; Muramatsu, Masami; Parker, Malcolm G.; Gustafsson, Jan-AakePharmacological Reviews (2006), 58 (4), 773-781CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. A review discusses the mechanism of transcriptional activation and functional roles of estrogen receptors in physiol. and disease. It also tackles structural features of the ligand-binding domain and current evaluation of SERMs as medicines.
- 450Hewitt, S. C.; Korach, K. S. Estrogen Receptors: New Directions in the New Millennium. Endocr. Rev. 2018, 39 (5), 664– 675, DOI: 10.1210/er.2018-00087[Crossref], [PubMed], [CAS], Google Scholar457https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mbnt1CmsQ%253D%253D&md5=f3e205139f5c634223569c1006c060acEstrogen Receptors: New Directions in the New MillenniumHewitt Sylvia C; Korach Kenneth SEndocrine reviews (2018), 39 (5), 664-675 ISSN:.Nineteen years have passed since our previous review in this journal in 1999 regarding estrogen receptors. At that time, we described the current assessments of the physiological activities of estrogen and estrogen receptors. Since that time there has been an explosion of progress in our understanding of details of estrogen receptor-mediated processes from the molecular and cellular level to the whole organism. In this review we discuss the basic understanding of estrogen signaling and then elaborate on the progress and current understanding of estrogen receptor actions that have developed using new models and continuing clinical studies.
- 451Dupont, S.; Krust, A.; Gansmuller, A.; Dierich, A.; Chambon, P.; Mark, M. Effect of Single and Compound Knockouts of Estrogen Receptors Alpha (ERalpha) and Beta (ERbeta) on Mouse Reproductive Phenotypes. Development 2000, 127 (19), 4277– 4291, DOI: 10.1242/dev.127.19.4277[Crossref], [PubMed], [CAS], Google Scholar458https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXotVWisbY%253D&md5=b19ca01d70bf99b001292b3bb7161169Effect of single and compound knockouts of estrogen receptors α (ERα) and β (ERβ) on mouse reproductive phenotypesDupont, Sonia; Krust, Andree; Gansmuller, Anne; Dierich, Andree; Chambon, Pierre; Mark, ManuelDevelopment (Cambridge, United Kingdom) (2000), 127 (19), 4277-4291CODEN: DEVPED; ISSN:0950-1991. (Company of Biologists Ltd.)The functions of estrogen receptors (ERs) in mouse ovary and genital tracts were investigated by generating null mutants for ERα (ERαKO), ERβ (ERβKO) and both ERs (ERαβKO). All ERαKO females are sterile, whereas ERβKO females are either infertile or exhibit variable degrees of subfertility. Mast cells present in adult ERαKO and ERαβKO ovaries could participate in the generation of hemorrhagic cysts. Folliculogenesis proceeds normally up to the large antral stage in both ERαKO and ERβKO adults, whereas large antral follicles of ERα+/-/ERβKO and ERαβKO adults are markedly deficient in granulosa cells. Similarly, prematurely developed follicles found in prepubertal ERαKO ovaries appear normal, but their ERαβKO counterparts display only few granulosa cell layers. Upon superovulation treatment, all prepubertal ERαKO females form numerous preovulatory follicles of which the vast majority do not ovulate. The same treatment fails to elicit the formation of preovulatory follicles in half of the ERβKO mice and in all ERα+/-/ERβKO mice. These and other results reveal a functional redundancy between ERα and ERβ for ovarian folliculogenesis, and strongly suggest that ERβ plays an important role in mediating the stimulatory effects of estrogens on granulosa cell proliferation, ERα is not required for follicle growth under wild type conditions, while it is indispensable for ovulation, and ERα is also necessary for interstitial glandular cell development. The authors' data also indicate that ERβ exerts some function in ERαKO uterus and vagina. ERαβKO granulosa cells localized within degenerating follicles transform into cells displaying junctions that are unique to testicular Sertoli cells. From the distribution pattern of anti-Mullerian hormone (AMH) in ERαβKO ovaries, it is unlikely that an elevated AMH level is the cause of Sertoli cell differentiation. The authors' results also show that cell proliferation in the prostate and urinary bladder of old ERβKO and ERαβKO males is apparently normal.
- 452Lan, Y.-L.; Zhao, J.; Li, S. Update on the Neuroprotective Effect of Estrogen Receptor Alpha Against Alzheimer’s Disease. J. Alzheimer's Dis. 2015, 43 (4), 1137– 1148, DOI: 10.3233/JAD-141875[Crossref], [PubMed], [CAS], Google Scholar459https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFalt7zE&md5=491a95dc15d88d857a5219463bce4778Update on the Neuroprotective Effect of Estrogen Receptor Alpha Against Alzheimer's DiseaseLan, Yu-Long; Zhao, Jie; Li, ShaoJournal of Alzheimer's Disease (2015), 43 (4), 1137-1148CODEN: JADIF9; ISSN:1387-2877. (IOS Press)A review. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and disordered cognition. Women have a higher AD incidence than men, indicating that the declining estrogen levels during menopause may influence AD pathogenesis. However, the mechanism underlying estrogen's neuroprotective effect is not fully clarified and is complicated by the presence of several distinct estrogen receptor (ER) types and the identification of a growing no. of ER splice variants. Thus, a deeper anal. of ERs could elucidate the role of estrogen in age-related cognitive changes. Intracellular calcium signaling cascades play a pivotal role in ERα neuroprotection against AD. The ERα-mediated inhibition of Death domain-assocd. protein (Daxx) translocation and the combination of membrane ERα and caveolin in caveolae may protect against AD. Moreover, the voltage-dependent anion channel (VDAC)/ERα assocn. may be important for maintaining channel inactivation and may be relevant in neuronal preservation against Aβ injury. Addnl., ERα may prevent glutamate excitotoxic injury by Aβ through estrogen signaling mechanisms. ERα and IGF-IR co-activation may mediate neuroprotection, and many other growth factors and intracellular signaling responses triggered by ERα may also play important roles in this process. Furthermore, details regarding the genes and mRNA variants of ERα that are expressed in different parts of the human organs have been clarified recently. Therefore, here we review the literature to clarify the neuroprotective role of ERα. This review focuses on the potential mechanisms mediated by ERα in the intracellular signaling events in nervous system cells, thereby clarifying ERα-mediated protection against AD.
- 453Chakrabarti, M.; Haque, A.; Banik, N. L.; Nagarkatti, P.; Nagarkatti, M.; Ray, S. K. Estrogen Receptor Agonists for Attenuation of Neuroinflammation and Neurodegeneration. Brain Res. Bull. 2014, 109, 22– 31, DOI: 10.1016/j.brainresbull.2014.09.004[Crossref], [PubMed], [CAS], Google Scholar460https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Wjsr%252FK&md5=a9f6710232c3b28dcb6316bd863bba6cEstrogen receptor agonists for attenuation of neuroinflammation and neurodegenerationChakrabarti, Mrinmay; Haque, Azizul; Banik, Naren L.; Nagarkatti, Prakash; Nagarkatti, Mitzi; Ray, Swapan K.Brain Research Bulletin (2014), 109 (), 22-31CODEN: BRBUDU; ISSN:0361-9230. (Elsevier)Recent results from lab. investigations and clin. trials indicate important roles for estrogen receptor (ER) agonists in protecting the central nervous system (CNS) from noxious consequences of neuroinflammation and neurodegeneration. Neurodegenerative processes in several CNS disorders including spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD) are assocd. with activation of microglia and astrocytes, which drive the resident neuroinflammatory response. During neurodegenerative processes, activated microglia and astrocytes cause deleterious effects on surrounding neurons. The inhibitory activity of ER agonists on microglia activation might be a beneficial therapeutic option for delaying the onset or progression of neurodegenerative injuries and diseases. Recent studies suggest that ER agonists can provide neuroprotection by modulation of cell survival mechanisms, synaptic reorganization, regenerative responses to axonal injury, and neurogenesis process. The anti-inflammatory and neuroprotective actions of ER agonists are mediated mainly via two ERs known as ERα and ERβ. Although some studies have suggested that ER agonists may be deleterious to some neuronal populations, the potential clin. benefits of ER agonists for augmenting cognitive function may triumph over the assocd. side effects. Also, understanding the modulatory activities of ER agonists on inflammatory pathways will possibly lead to the development of selective anti-inflammatory mols. with neuroprotective roles in different CNS disorders such as SCI, MS, PD, and AD in humans. Future studies should be concd. on finding the most plausible mol. pathways for enhancing protective functions of ER agonists in treating neuroinflammatory and neurodegenerative injuries and diseases in the CNS.
- 454Pike, C. J.; Carroll, J. C.; Rosario, E. R.; Barron, A. M. Protective Actions of Sex Steroid Hormones in Alzheimer’s Disease. Frontiers in Neuroendocrinology 2009, 30 (2), 239– 258, DOI: 10.1016/j.yfrne.2009.04.015[Crossref], [PubMed], [CAS], Google Scholar461https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnsV2rsbw%253D&md5=72830b36e50e6132298ed4e8c9954125Protective actions of sex steroid hormones in Alzheimer's diseasePike, Christian J.; Carroll, Jenna C.; Rosario, Emily R.; Barron, Anna M.Frontiers in Neuroendocrinology (2009), 30 (2), 239-258CODEN: FNEDA7; ISSN:0091-3022. (Elsevier B. V.)A review. Risk for Alzheimer's disease (AD) is assocd. with age-related loss of sex steroid hormones in both women and men. In post-menopausal women, the precipitous depletion of estrogens and progestogens is hypothesized to increase susceptibility to AD pathogenesis, a concept largely supported by epidemiol. evidence but refuted by some clin. findings. Exptl. evidence suggests that estrogens have numerous neuroprotective actions relevant to prevention of AD, in particular promotion of neuron viability and redn. of β-amyloid accumulation, a crit. factor in the initiation and progression of AD. Recent findings suggest neural responsiveness to estrogen can diminish with age, reducing neuroprotective actions of estrogen and, consequently, potentially limiting the utility of hormone therapies in aged women. In addn., estrogen neuroprotective actions are also modulated by progestogens. Specifically, continuous progestogen exposure is assocd. with inhibition of estrogen actions whereas cyclic delivery of progestogens may enhance neural benefits of estrogen. In recent years, emerging literature has begun to elucidate a parallel relationship of sex steroid hormones and AD risk in men. Normal age-related testosterone loss in men is assocd. with increased risk to several diseases including AD. Like estrogen, testosterone has been established as an endogenous neuroprotective factor that not only increases neuronal resilience against AD-related insults, but also reduces β-amyloid accumulation. Androgen neuroprotective effects are mediated both directly by activation of androgen pathways and indirectly by aromatization to estradiol and initiation of protective estrogen signaling mechanisms. The successful use of hormone therapies in aging men and women to delay, prevent, and or treat AD will require addnl. research to optimize key parameters of hormone therapy and may benefit from the continuing development of selective estrogen and androgen receptor modulators.
- 455Boada, M.; Antunez, C.; López-Arrieta, J.; Caruz, A.; Moreno-Rey, C.; Ramírez-Lorca, R.; Morón, F. J.; Hernández, I.; Mauleón, A.; Rosende-Roca, M.; Martínez-Lage, P.; Marín, J.; Tárraga, L.; Alegret, M.; Pedrajas, J. R.; Urda, N.; Royo, J. L.; Saez, M. E.; Gayán, J.; González-Pérez, A.; Real, L. M.; Ruiz, A.; Galán, J. J. Estrogen Receptor Alpha Gene Variants Are Associated with Alzheimer’s Disease. Neurobiol. Aging 2012, 33 (1), 198.e15– 198.e24, DOI: 10.1016/j.neurobiolaging.2010.06.016
- 456Goodman, Y.; Bruce, A. J.; Cheng, B.; Mattson, M. P. Estrogens Attenuate and Corticosterone Exacerbates Excitotoxicity, Oxidative Injury, and Amyloid β-Peptide Toxicity in Hippocampal Neurons. J. Neurochem. 1996, 66 (5), 1836– 1844, DOI: 10.1046/j.1471-4159.1996.66051836.x[Crossref], [PubMed], [CAS], Google Scholar463https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XisVSkurs%253D&md5=e78a114c34218cf81c2808c41886c157Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neuronsGoodman, Yadong; Bruce, Annadora J.; Cheng, Bin; Mattson, Mark P.Journal of Neurochemistry (1996), 66 (5), 1836-44CODEN: JONRA9; ISSN:0022-3042. (Lippincott-Raven)Steroid hormones, particularly estrogens and glucocorticoids, may play roles in the pathogenesis of neurodegenerative disorders, but their mechanisms of action are not known. We report that estrogens protect cultured hippocampal neurons against glutamate toxicity, glucose deprivation, FeSO4 toxicity, and amyloid β-peptide (Aβ) toxicity. The toxicity of each insult was significantly attenuated in cultures pretreated for 2 h with 100 nM-10 μM 17β-estradiol, estriol, or progesterone. In contrast, corticosterone exacerbated neuronal injury induced by glutamate, FeSO4, and Aβ. Several other steroids, including testosterone, aldosterone, and vitamin D, had no effect on neuronal vulnerability to the different insults. The protective actions of estrogens and progesterone were not blocked by actinomycin D or cycloheximide. Lipid peroxidn. induced by FeSO4 and Aβ was significantly attenuated in neurons and isolated membranes pretreated with estrogens and progesterone, suggesting that these steroids possess antioxidant activities. Estrogens and progesterone also attenuated Aβ- and glutamate-induced elevation of intracellular free Ca2+ concns. We conclude that estrogens, progesterone, and corticosterone can directly affect neuronal vulnerability to excitotoxic, metabolic, and oxidative insults, suggesting roles for these steroids in several different neurodegenerative disorders.
- 457Green, P. S.; Gridley, K. E.; Simpkins, J. W. Estradiol Protects against β-Amyloid (25–35)-Induced Toxicity in SK-N-SH Human Neuroblastoma Cells. Neurosci. Lett. 1996, 218 (3), 165– 168, DOI: 10.1016/S0304-3940(96)13148-7[Crossref], [PubMed], [CAS], Google Scholar464https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xnt1Ohsrw%253D&md5=49d37d6f03ba0c70aec07c67bf46de0eEstradiol protects against β-amyloid (25-35)-induced toxicity in SK-N-SH human neuroblastoma cellsGreen, Pattie S.; Gridley, Kelly E.; Simpkins, James W.Neuroscience Letters (1996), 218 (3), 165-168CODEN: NELED5; ISSN:0304-3940. (Elsevier)Estrogen-replacement therapy has been assocd. with a reduced incidence of Alzheimer's disease (AD) and improved cognition in several small open clin. trials. We assessed the possibility that estrogens may reduce toxicity of β-amyloid (Aβ) by testing the effects of β-estradiol on the toxicity of the neurotoxic fragment of β-amyloid (Aβ 25-35) in SK-N-SH neuroblastoma cells. Aβ 25-35 caused a dose-dependent death in SK-N-SH cells with a LD50 of 28.9 μM. In cultures simultaneously exposed to 20 μM Aβ and 17 β-estradiol (2 nM), Aβ-induced toxicity was reduced by 83 and 51% in two sep. studies. Further studies show that 0.2 nM 17β-estradiol was as effective as the 2 nM concn. 17α-Estradiol (2 nM) conferred neuroprotection equiv. to that of 17β-estradiol. These data support the hypothesis that estrogens reduce β-amyloid toxicity and this may help explain the beneficial effects of estrogens in AD.
- 458Behl, C.; Widmann, M.; Trapp, T.; Holsboer, F. 17-β Estradiol Protects Neurons from Oxidative Stress-Induced Cell Death in Vitro. Biochem. Biophys. Res. Commun. 1995, 216 (2), 473– 482, DOI: 10.1006/bbrc.1995.2647[Crossref], [PubMed], [CAS], Google Scholar465https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXptlentLY%253D&md5=5e63822d03088d13f78a3781649a232017β-Estradiol protects neurons from oxidative stress-induced cell death in vitroBehl, Christian; Widmann, Martina; Trapp, Thorsten; Holsboer, FlorianBiochemical and Biophysical Research Communications (1995), 216 (2), 473-82CODEN: BBRCA9; ISSN:0006-291X. (Academic)The potential antioxidant activity of 17-β estradiol and other steroid hormones in neuronal cells was investigated by studying oxidative stress-induced cell death caused by the neurotoxins amyloid β protein, hydrogen peroxide and glutamate in the clonal mouse hippocampal cell line HT22. Preincubation of the cells with 10-5 M 17-β estradiol prior to addn. of the neurotoxins prevented oxidative stress-induced cell damage and ultimately cell death, as detected with cell viability (MTT) and cell lysis (trypan blue exclusion/cell counting; propidium iodide staining) assays. At the DNA level, 17-β estradiol blocked the DNA degrdn. caused by glutamate. Other steroid hormones, such as progesterone, aldosterone, corticosterone and the steroid precursor cholesterol, did not protect the cells. The neuronal protection afforded by 17-β estradiol was estrogen receptor-independent. These data demonstrate a potent neuroprotective activity of the antioxidant 17-β estradiol, which may have implications for the prevention and treatment of Alzheimer's disease.
- 459Singer, C. A.; Rogers, K. L.; Strickland, T. M.; Dorsa, D. M. Estrogen Protects Primary Cortical Neurons from Glutamate Toxicity. Neurosci. Lett. 1996, 212 (1), 13– 16, DOI: 10.1016/0304-3940(96)12760-9[Crossref], [PubMed], [CAS], Google Scholar466https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XktlSitLk%253D&md5=a80f396129180325016450a9513e7a56Estrogen protects primary cortical neurons from glutamate toxicitySinger, Cherie A.; Rogers, Keith L.; Strickland, Tamara M.; Dorsa, Daniel M.Neuroscience Letters (1996), 212 (1), 13-16CODEN: NELED5; ISSN:0304-3940. (Elsevier)The gonadal steroid estrogen has been shown to affect neuronal growth, differentiation and survival. We examd. the ability of estrogen to protect primary cortical neurons from toxicity induced by the excitatory neurotransmitter glutamate. In these expts., a 24-h pretreatment with 15 and 50 nM 17β-estradiol significantly reduced cellular lactate dehydrogenase (LDH) release from primary cortical neurons, indicating that neurons treated with 17β-estradiol were protected from a toxic glutamate exposure. Pretreatment with related steroids such as progesterone, dihydrotestosterone, dexamethasone or cholesterol did not significantly decrease LDH release. The anti-estrogen tamoxifen blocked the protective effects of 17β-estradiol suggesting that a classical steroid hormone receptor may be involved in the mechanism subserving estrogen neuroprotection during glutamate toxicity.
- 460Zhang, Q.-G.; Raz, L.; Wang, R.; Han, D.; De Sevilla, L.; Yang, F.; Vadlamudi, R. K.; Brann, D. W. Estrogen Attenuates Ischemic Oxidative Damage Via an Estrogen Receptor α-Mediated Inhibition of NADPH Oxidase Activation. J. Neurosci. 2009, 29 (44), 13823– 13836, DOI: 10.1523/JNEUROSCI.3574-09.2009[Crossref], [PubMed], [CAS], Google Scholar467https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVSmsbjN&md5=e72641ec196dc6316e6c55f1b7713ae0Estrogen attenuates ischemic oxidative damage via an estrogen receptor α-mediated inhibition of NADPH oxidase activationZhang, Quan-Guang; Raz, Limor; Wang, Ruimin; Han, Dong; De Sevilla, Liesl; Yang, Fang; Vadlamudi, Ratna K.; Brann, Darrell W.Journal of Neuroscience (2009), 29 (44), 13823-13836CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)The goal of this study was to elucidate the mechanisms of 17β-estradiol (E2) antioxidant and neuroprotective actions in stroke. The results reveal a novel extranuclear receptor-mediated antioxidant mechanism for E2 during stroke, as well as a hypersensitivity of the CA3/CA4 region to ischemic injury after prolonged hypoestrogenicity. E2 neuroprotection was shown to involve a profound attenuation of NADPH oxidase activation and superoxide prodn. in hippocampal CA1 pyramidal neurons after stroke, an effect mediated by extranuclear estrogen receptor α (ERα)-mediated nongenomic signaling, involving Akt activation and subsequent phosphorylation/inactivation of Rac1, a factor crit. for activation of NOX2 NADPH oxidase. Intriguingly, E2 nongenomic signaling, antioxidant action, and neuroprotection in the CA1 region were lost after long-term E2 deprivation, and this loss was tissue specific because the uterus remained responsive to E2. Correspondingly, a remarkable loss of ERα, but not ERβ, was obsd. in the CA1 after long-term E2 deprivation, with no change obsd. in the uterus. As a whole, the study reveals a novel, membrane-mediated antioxidant mechanism in neurons by E2 provides support and mechanistic insights for a "crit. period" of E2 replacement in the hippocampus and demonstrates a heretofore unknown hypersensitivity of the CA3/CA4 to ischemic injury after prolonged hypoestrogenicity.
- 461Spampinato, S. F.; Molinaro, G.; Merlo, S.; Iacovelli, L.; Caraci, F.; Battaglia, G.; Nicoletti, F.; Bruno, V.; Sortino, M. A. Estrogen Receptors and Type 1 Metabotropic Glutamate Receptors Are Interdependent in Protecting Cortical Neurons against β-Amyloid Toxicity. Mol. Pharmacol. 2012, 81 (1), 12– 20, DOI: 10.1124/mol.111.074021[Crossref], [PubMed], [CAS], Google Scholar468https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtVSktro%253D&md5=752d10d11565e583471f5b1595bf19d9Estrogen receptors and type 1 metabotropic glutamate receptors are interdependent in protecting cortical neurons against β-amyloid toxicitySpampinato, Simona Federica; Molinaro, Gemma; Merlo, Sara; Iacovelli, Luisa; Caraci, Filippo; Battaglia, Giuseppe; Nicoletti, Ferdinando; Bruno, Valeria; Sortino, Maria AngelaMolecular Pharmacology (2012), 81 (1), 12-20CODEN: MOPMA3; ISSN:1521-0111. (American Society for Pharmacology and Experimental Therapeutics)We examd. the interaction between estrogen receptors (ERs) and type 1 metabotropic glutamate receptors (mGlu1 receptors) in mechanisms of neurodegeneration/neuroprotection using mixed cultures of cortical cells challenged with β-amyloid peptide. Both receptors were present in neurons, whereas only ERα but not mGlu1 receptors were found in astrocytes. Addn. of 17β-estradiol (17βE2) protected cultured neurons against amyloid toxicity, and its action was mimicked by the selective ERα agonist, 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) as well as by a cell-impermeable bovine serum albumin conjugate of 17βE2. The selective ERβ agonist, diarylpropionitrile (DPN), was only slightly neuroprotective. The mGlu1/5 receptor agonist, 3,5-dihydroxyphenylglycine (DHPG), was also neuroprotective against amyloid toxicity, and its action was abolished by the mGlu1 receptor antagonist, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ 16259685). Neuroprotection by 17βE2 or PPT (but not DPN) and DHPG was less than additive, suggesting that ERα and mGlu1 receptors activate the same pathway of cell survival. More important, neuroprotection by 17βE2 was abolished not only by the ER antagonist fulvestrant (ICI 182,780) but also by JNJ 16259685, and neuroprotection by DHPG was abolished by ICI 182,780. ERα and mGlu1 receptors were also interdependent in activating the phosphatidylinositol-3-kinase pathway, and pharmacol. blockade of this pathway abolished neuroprotection by 17βE2, DHPG, or their combination. These data provide the first evidence that ERα and mGlu1 receptors critically interact in promoting neuroprotection, information that should be taken into account when the impact of estrogen on neurodegeneration assocd. with central nervous system disorders is examd.
- 462Pike, C. J. Estrogen Modulates Neuronal Bcl-XL Expression and β-Amyloid-Induced Apoptosis: Relevance to Alzheimer’s Disease. J. Neurochem. 1999, 72 (4), 1552– 1563, DOI: 10.1046/j.1471-4159.1999.721552.x[Crossref], [PubMed], [CAS], Google Scholar469https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXitFCksLY%253D&md5=817658b7548f99e9a6ce3e079ce94d1bEstrogen modulates neuronal Bcl-XL expression and β-amyloid-induced apoptosis: relevance to Alzheimer's diseasePike, Christian J.Journal of Neurochemistry (1999), 72 (4), 1552-1563CODEN: JONRA9; ISSN:0022-3042. (Lippincott Williams & Wilkins)Recent findings indicate that estrogen is neuroprotective, a cellular effect that may contribute to its clin. benefits in delaying the development of Alzheimer's disease. The authors identify a novel neuronal action of estrogen that may contribute to its neuroprotective mechanism(s). Specifically, the authors report that estrogen significantly increases the expression of the anti-apoptotic protein Bcl-xL in cultured hippocampal neurons. This effect presumably reflects classic estrogen transcriptional regulation, as the authors identified a putative estrogen response element in the bcl-x gene. Estrogen-induced enhancement of Bcl-xL is assocd. with a redn. in measures of β-amyloid-induced apoptosis, including inhibition of both caspase-mediated proteolysis and neurotoxicity. A similar relationship between estrogen, Bcl-xL expression, and resistance to degeneration was also obsd. in human hippocampus. The authors report neuronal colocalization of estrogen receptor and Bcl-xL immunoreactivities that is most prominent in hippocampal subfield CA3, a region that shows relatively little immunoreactivity to paired helical filament-1, a marker of Alzheimer's disease neurodegeneration. These data suggest a novel mechanism of estrogen neuroprotection that may be relevant to estrogen's suggested ability to modulate neuronal viability across the life span, from neural sexual differentiation and development through age-related neurodegenerative conditions.
- 463Yao, M.; Nguyen, T.-V. V.; Pike, C. J. Estrogen Regulates Bcl-w and Bim Expression: Role in Protection against β-Amyloid Peptide-Induced Neuronal Death. J. Neurosci. 2007, 27 (6), 1422– 1433, DOI: 10.1523/JNEUROSCI.2382-06.2007[Crossref], [PubMed], [CAS], Google Scholar470https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhvFCrurY%253D&md5=c7b0ec00e418580d5f5718618cdbc4efEstrogen regulates Bcl-w and bim expression: role in protection against β-amyloid peptide-induced neuronal deathYao, Mingzhong; Nguyen, Thuy-Vi V.; Pike, Christian J.Journal of Neuroscience (2007), 27 (6), 1422-1433CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Estrogen is neuroprotective against a variety of insults, including β-amyloid peptide (Aβ); however, the underlying mechanism(s) is not fully understood. Here, we report that 17β-estradiol (E2) selectively regulates neuronal expression of the Bcl-2 family (bcl-2, bcl-x, bcl-w, bax, bak, bad, bik, bnip3, bid, and bim). In primary cerebrocortical neuron cultures under basal conditions, we observe that E2 upregulates expression of antiapoptotic Bcl-w and downregulates expression of proapoptotic Bim in an estrogen receptor (ER)-dependent manner. In the presence of toxic levels of Aβ, we observe that E2 attenuates indexes of neuronal apoptosis: c-Jun N-terminal kinase (JNK)-dependent downregulation of Bcl-w and upregulation of Bim, mitochondrial release of cytochrome c and Smac, and cell death. These neuroprotective effects of E2 against Aβ-induced apoptosis are mimicked by the JNK inhibitor SP 600125. In addn., E2 attenuates Aβ-induced JNK phosphorylation in an ER-dependent manner, but does not affect basal levels of JNK phosphorylation. These results suggest that E2 may reduce Aβ-induced neuronal apoptosis at least in part by two complementary pathways: (1) ER-dependent, JNK-independent upregulation of Bcl-w and downregulation of Bim under basal conditions, and (2) ER-dependent inhibition of Aβ-induced JNK activation and subsequent JNK-dependent downregulation of Bcl-w and upregulation of Bim, resulting in mitochondrial release of cytochrome c and Smac and eventual cell death. These data provide new understanding into the mechanisms contributing to estrogen neuroprotection, a neural function with potential therapeutic relevance to Alzheimer's disease.
- 464Zhao, L.; Wu, T.-W.; Brinton, R. D. Estrogen Receptor Subtypes Alpha and Beta Contribute to Neuroprotection and Increased Bcl-2 Expression in Primary Hippocampal Neurons. Brain Res. 2004, 1010 (1–2), 22– 34, DOI: 10.1016/j.brainres.2004.02.066[Crossref], [PubMed], [CAS], Google Scholar471https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjs1Wltbw%253D&md5=ff6963cb0c1aa4be3107225d24959c67Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neuronsZhao, Liqin; Wu, Tzu-wei; Brinton, Roberta DiazBrain Research (2004), 1010 (1,2), 22-34CODEN: BRREAP; ISSN:0006-8993. (Elsevier Science B.V.)Estrogen receptor (ER) mediated neuroprotection has been demonstrated in both in vitro and in vivo model systems. However, the relative contribution by either ER subtype, ERα or ERβ, to estrogen-induced neuroprotection remains unresolved. To address this question, the authors investigated the impact of selective ER agonists for either ERα, PPT, or ERβ, DPN, to prevent neurodegeneration in cultured hippocampal neurons exposed to excitotoxic glutamate. Using three indicators of neuronal viability and survival, the authors demonstrated that both the ERα selective agonist PPT and the ERβ selective agonist DPN protected hippocampal neurons against glutamate-induced cell death in a dose-dependent manner, with the maximal response occurring at 100 pM. Further analyses showed that both PPT and DPN enhanced Bcl-2 expression in hippocampal neurons, with an efficacy comparable to their neuroprotective capacity. Collectively, the present data indicate that activation of either ERα or ERβ can promote neuroprotection in hippocampal neurons, suggesting that both receptor subtypes could be involved in estrogen neuroprotection. As ERβ is highly expressed in the brain and has little or no expression in the breast or uterus, discovery and design of ERβ selective mols. could provide a strategy for activating the beneficial effects of estrogen in the brain without activating untoward effects of estrogen in reproductive organs.
- 465Suwanna, N.; Thangnipon, W.; Soi-ampornkul, R. Neuroprotective Effects of Diarylpropionitrile against β-Amyloid Peptide-Induced Neurotoxicity in Rat Cultured Cortical Neurons. Neurosci. Lett. 2014, 578, 44– 49, DOI: 10.1016/j.neulet.2014.06.029[Crossref], [PubMed], [CAS], Google Scholar472https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Kltb%252FE&md5=b12717240552572671b8c2de25358a6bNeuroprotective effects of diarylpropionitrile against β-amyloid peptide-induced neurotoxicity in rat cultured cortical neuronsSuwanna, Nirut; Thangnipon, Wipawan; Soi-ampornkul, RungtipNeuroscience Letters (2014), 578 (), 44-49CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Alzheimer's disease is a major cause of dementia in the elderly that involves a β-amyloid peptide (Aβ)-induced cascade of an increase in oxidative damage and inflammation. The present study demonstrated the neuroprotective effects of diarylpropionitrile (DPN), a non-steroidal estrogen receptor β selective ligand, against 10 μM Aβ1-42-induced oxidative stress and inflammation in primary rat cortical cell culture. Pre-treatment with 1-100 nM DPN significantly decreased neuronal cell death by increasing cell viability through a significant attenuation in the reactive oxygen species level, downregulation of pro-apoptotic activated caspase-3 and Bax, and upregulation of anti-apoptotic Bcl-2, thereby mitigating apoptotic morphol. alterations. DPN pre-treatment decreased the expression levels of pro-inflammatory cytokines IL-1β and IL-6 through attenuation of Aβ1-42-induced phosphorylation of mitogen-activated protein kinases JNK and p38. In addn., DPN enhanced ERK1/2 and Akt phosphorylation depressed by Aβ1-42. These findings suggest that DPN protects neurons from Aβ1-42-induced neurotoxicity through a variety of mechanisms, ranging from anti-oxidn., anti-apoptosis, through to anti-inflammation.
- 466Mateos, L.; Persson, T.; Kathozi, S.; Gil-Bea, F. J.; Cedazo-Minguez, A. Estrogen Protects against Amyloid-β Toxicity by Estrogen Receptor α-Mediated Inhibition of Daxx Translocation. Neurosci. Lett. 2012, 506 (2), 245– 250, DOI: 10.1016/j.neulet.2011.11.016[Crossref], [PubMed], [CAS], Google Scholar473https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlOkuw%253D%253D&md5=49eb420a010d6800be9d7bfe8e45dacbEstrogen protects against amyloid-β toxicity by estrogen receptor α-mediated inhibition of Daxx translocationMateos, Laura; Persson, Torbjoern; Katoozi, Shirin; Gil-Bea, Francisco Javier; Cedazo-Minguez, AngelNeuroscience Letters (2012), 506 (2), 245-250CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Estrogen was shown to promote neuronal survival against several neurotoxic insults including β-amyloid (Aβ). The proposed mechanism includes the activation of the mitogen activated protein kinase/extracellular signal-regulated kinase (Mapk/Erk), phosphatidylinositol 3-kinase/Akt pathways and the upregulation of antiapoptotic proteins. On the other hand, Aβ neurotoxicity depends on the activation of apoptosis signal-regulating kinase 1 (Ask1), and both Ask1 activity and Aβ toxicity are inhibited by thioredoxin-1 (Trx1). Here, we explored the possibility that estrogen could protect cells against Aβ(1-42) toxicity by inhibiting the Ask1 cascade or by modulating Trx1. Cytosolic translocation of death-assocd. protein Daxx was used as indicator of Ask1 activity. Using human SH-SY5Y neuroblastoma cells, 17β-estradiol (E2) and specific agonists for estrogen receptor (ER) α or β we demonstrated that nM concns. of E2 protected against Aβ(1-42) by a mechanism depending upon ERα stimulation, Akt activation and Ask1 inhibition. Moreover, this protection would occur independently of ERβ and the induction of Trx1 expression. Our results emphasize the importance of Ask1 cascade in Aβ toxicity, and of ERα and Ask1 as targets for developing new neuroprotective drugs.
- 467Witty, C. F.; Gardella, L. P.; Perez, M. C.; Daniel, J. M. Short-Term Estradiol Administration in Aging Ovariectomized Rats Provides Lasting Benefits for Memory and the Hippocampus: A Role for Insulin-like Growth Factor-I. Endocrinology 2013, 154 (2), 842– 852, DOI: 10.1210/en.2012-1698[Crossref], [PubMed], [CAS], Google Scholar474https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitVehtL0%253D&md5=087bda417de535ad79bb2ece0eb345daShort-term estradiol administration in aging ovariectomized rats provides lasting benefits for memory and the hippocampus: a role for insulin-like growth factor-IWitty, Christine F.; Gardella, Layne P.; Perez, Maria C.; Daniel, Jill M.Endocrinology (2013), 154 (2), 842-852CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)The authors previously demonstrated that aged ovariectomized rats that had received prior estradiol treatment in middle age exhibited enhanced spatial memory and increased levels of estrogen receptor (ER)-α in the hippocampus long after estradiol treatment was terminated. The implication for cognition of increased levels of ERα resulting from prior estradiol exposure is unknown. In the absence of estrogens, growth factors, including IGF-I, can induce ERα-mediated transcription through ligand-independent mechanisms. The authors' current goal was to det. whether IGF-I mediates the ability of short-term exposure to estradiol to exert long-term effects on cognition and the hippocampus of aging females. Ovariectomized middle-aged rats were implanted with estradiol or cholesterol vehicle capsules. After 40 days, all capsules were removed and drug treatments were initiated. Half of each hormone treatment group received chronic intracerebroventricular delivery of the IGF-I receptor antagonist JB1, and the other half received artificial cerebrospinal fluid vehicle. Rats were tested on a spatial memory radial-arm maze task and hippocampi were immunostained for proteins of interest by Western blotting. As expected, previous treatment with estradiol enhanced spatial memory and increased levels of ERα in the hippocampus. JB1 reversed these effects. Previous treatment with estradiol resulted in lasting increases in levels of IGF-I receptors and phosphorylation of ERK/MAPK, a downstream signaling mol. of both ERα and IGF-I receptors, and increased levels of the ERα-regulated protein, choline acetyltransferase. JB1 blocked effects on ERK/MAPK and choline acetyltransferase. Results indicate that activation of IGF-I receptors is necessary for prior estradiol exposure to exert lasting impact on the hippocampus and memory.
- 468Azcoitia, I.; Sierra, A.; Garcia-Segura, L. M. Neuroprotective Effects of Estradiol in the Adult Rat Hippocampus: Interaction with Insulin-like Growth Factor-I Signalling. J. Neurosci. Res. 1999, 58 (6), 815– 822, DOI: 10.1002/(SICI)1097-4547(19991215)58:6<815::AID-JNR8>3.0.CO;2-R[Crossref], [PubMed], [CAS], Google Scholar475https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXnvF2gs7Y%253D&md5=98ad29ca2408a8ee569b67f47a0ad673Neuroprotective effects of estradiol in the adult rat hippocampus: interaction with insulin-like growth factor-I signalingAzcoitia, Inigo; Sierra, Amanda; Garcia-Segura, Luis M.Journal of Neuroscience Research (1999), 58 (6), 815-822CODEN: JNREDK; ISSN:0360-4012. (Wiley-Liss, Inc.)We have previously shown that 17-β-estradiol protects neurons in the dentate gyrus from kainic acid-induced death in vivo. To analyze whether this effect is mediated through estrogen receptors and through cross-talk between steroid and insulin-like growth factor (IGF) systems, we have concomitantly administered antagonists of estrogen receptor (ICI 182780) or the IGF-I receptor (JB 1) with estradiol. In addn., we have also administered IGF-I with or without the estrogen receptor antagonist. JB 1 (20 μg/mL), ICI 182780 (10-7 M), and IGF-I (100 μg/mL) were delivered into the left lateral ventricle of young ovariectomized rats via an Alzet osmotic minipump (0.5 μL/h) for 2 wk. All rats received kainic acid (7 mg/kg) or vehicle i.p. injections at day 7 after minipump implant. Also on day 7, rats treated i.c.v. with only ICI 182780 or JB 1 received a single i.p. injection of 17-β-estradiol (150 μg/rat) or vehicle. On day 14 after minipump implant, the rats were killed, brains processed, and the no. of surviving hilar neurons estd. by the optical disector technique. Both IGF-I and estradiol treatments resulted in over 90% survival of hilar neurons. The neuroprotective action of estradiol was blocked by ICI 182780 and by JB 1. Furthermore, IGF-I enhancement of neuronal survival was significantly reduced by ICI 182780. These results indicate that in this model of hippocampal lesion, the neuroprotective effect of estradiol depends both on estrogen receptors and IGF-I receptors, while the protection exerted by IGF-I depends also on estrogen receptors. In conclusion, an interaction of estrogen receptor and IGF-I receptor signaling may mediate neuroprotection in the adult rat hippocampus.
- 469Rosario, E. R.; Ramsden, M.; Pike, C. J. Progestins Inhibit the Neuroprotective Effects of Estrogen in Rat Hippocampus. Brain Res. 2006, 1099 (1), 206– 210, DOI: 10.1016/j.brainres.2006.03.127[Crossref], [PubMed], [CAS], Google Scholar476https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XntlWitb8%253D&md5=cf3cb4002fdd213b06f68397fb044f02Progestins inhibit the neuroprotective effects of estrogen in rat hippocampusRosario, Emily R.; Ramsden, Martin; Pike, Christian J.Brain Research (2006), 1099 (1), 206-210CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)Although estrogen has beneficial actions in brain, recent clin. trials demonstrated adverse neural effects of hormone therapy in postmenopausal women. The cause(s) of this disconnect between exptl. and clin. findings may include unanticipated effects of progestins. We report that both natural progesterone and the clin. progestin medroxyprogesterone acetate block estrogen neuroprotection. These findings underscore the need to evaluate neural actions of progestins in the rational design of hormone therapy.
- 470Carroll, J. C.; Rosario, E. R.; Pike, C. J. Progesterone Blocks Estrogen Neuroprotection from Kainate in Middle-Aged Female Rats. Neurosci. Lett. 2008, 445 (3), 229– 232, DOI: 10.1016/j.neulet.2008.09.010[Crossref], [PubMed], [CAS], Google Scholar477https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1egur3N&md5=33762b16fcc7e931252e280d3a98c727Progesterone blocks estrogen neuroprotection from kainate in middle-aged female ratsCarroll, Jenna C.; Rosario, Emily R.; Pike, Christian J.Neuroscience Letters (2008), 445 (3), 229-232CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)The neuroprotective effects of estrogen in young adult rodents are well established. Less well understood is how estrogen neuroprotection is affected by aging and interactions with progesterone. In this study, we investigated the effects of estrogen and continuous progesterone, both alone and in combination, on hippocampal neuron survival following kainate lesion in 14-mo-old female rats entering reproductive senescence. Our results show that ovariectomy-induced hormone depletion did not significantly affect the extent of kainate-induced neuron loss. Treatment of ovariectomized rats with estrogen significantly reduced neuron loss, however this effect was blocked by co-administration of continuous progesterone. Treatment of ovariectomized rats with progesterone alone did not significantly affect kainate toxicity. These results provide new insight into factors that regulate estrogen neuroprotection, which has important implications for hormone therapy in postmenopausal women.
- 471Kim, H.; Bang, O. Y.; Jung, M. W.; Ha, S. D.; Hong, H. S.; Huh, K.; Kim, S. U.; Mook-Jung, I. Neuroprotective Effects of Estrogen against Beta-Amyloid Toxicity Are Mediated by Estrogen Receptors in Cultured Neuronal Cells. Neurosci. Lett. 2001, 302 (1), 58– 62, DOI: 10.1016/S0304-3940(01)01659-7[Crossref], [PubMed], [CAS], Google Scholar478https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXitF2qsb4%253D&md5=24001eff6137aacb47a88ebde5731830Neuroprotective effects of estrogen against beta-amyloid toxicity are mediated by estrogen receptors in cultured neuronal cellsKim, H.; Bang, O. Y.; Jung, M. W.; Ha, S. D.; Hong, H. S.; Huh, K.; Kim, S. U.; Mook-Jung, I.Neuroscience Letters (2001), 302 (1), 58-62CODEN: NELED5; ISSN:0304-3940. (Elsevier Science Ireland Ltd.)Although estrogen is known to exert beneficial effects on Alzheimer's disease, its underlying cellular mechanisms have not been clear. In this study the authors investigated whether or not neuroprotective effects of estrogen are mediated by estrogen receptors (ERs). Treatment of estrogen (1.8 nM) reduced beta-amyloid (Aβ)-induced death of ER-expressing W4 cells. This effect of estrogen was blocked by a specific ER blocker ICI 182,780. When estrogen was added to HT22 cells, which lack functional ERs, Aβ-induced cell death was not affected. Transfection of HT22 cells with human ERα, but not ERβ, restored protective action of estrogen against Aβ. Hoechst staining revealed that estrogen protected ERα-expressing cells by blocking Aβ-induced apoptosis. These results indicate that estrogen blocks Aβ-induced cell death via ERα-dependent pathways.
- 472Benvenuti, S.; Luciani, P.; Vannelli, G. B.; Gelmini, S.; Franceschi, E.; Serio, M.; Peri, A. Estrogen and Selective Estrogen Receptor Modulators Exert Neuroprotective Effects and Stimulate the Expression of Selective Alzheimer’s Disease Indicator-1, a Recently Discovered Antiapoptotic Gene, in Human Neuroblast Long-Term Cell Cultures. J. Clin. Endocrinol. Metab. 2005, 90 (3), 1775– 1782, DOI: 10.1210/jc.2004-0066[Crossref], [PubMed], [CAS], Google Scholar479https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXisVOhtbY%253D&md5=1528c789117960e1867deb4949c10a91Estrogen and selective estrogen receptor modulators exert neuroprotective effects and stimulate the expression of selective Alzheimer's disease indicator-1, a recently discovered antiapoptotic gene, in human neuroblast long-term cell culturesBenvenuti, Susanna; Luciani, Paola; Vannelli, Gabriella Barbara; Gelmini, Stefania; Franceschi, Elisa; Serio, Mario; Peri, AlessandroJournal of Clinical Endocrinology and Metabolism (2005), 90 (3), 1775-1782CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)According to the fact that Alzheimer's disease (AD) is more common in postmenopausal women, estrogen treatment has been proposed. Exptl. studies, still mostly performed using animal models, demonstrated that estrogen exerts neuroprotective effects. We previously established neuroblast long-term cell cultures from human fetal olfactory epithelium. In the present study, we addressed the role of estrogen in these unique human cells, which express both the estrogen receptor (ER)-α and ERβ. We found that 17β-estradiol (17βE2) and the selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen exerted neuroprotective effects, which were independent of cell proliferation, by increasing resistance against β-amyloid-induced toxicity, with the exception of the highest concns. of raloxifene (10 and 100 nM). In addn., 17βE2 exposure protected from oxidative stress, reduced apoptosis, and increased the expression of the catalytic subunit of telomerase. Furthermore, we evaluated by quant. real-time RT-PCR whether estrogen/SERMs modulate the expression of the recently discovered seladin-1 (selective AD indicator-1) gene, which exerts neuroprotective effects and is down-regulated in AD-vulnerable brain regions. 17βE2 (100 pM to 100 nM) and SERMs (1 nM) significantly increased the amt. of seladin-1 mRNA. Conversely, 10 and 100 nM raloxifene reduced the expression of seladin-1. The effect of estrogen appears mainly mediated by ERα because the selective ERα agonist propylpyrazole-triol detd. a much greater increase of seladin-1 expression than the ERβ agonist diarylpropionitrile. Our results add new evidence, using human neuronal cells, for a beneficial effect of estrogen in preventing neurodegenerative diseases and suggest for the first time that seladin-1 may mediate this effect.
- 473Mize, A. L.; Young, L. J.; Alper, R. H. Uncoupling of 5-HT1A Receptors in the Brain by Estrogens: Regional Variations in Antagonism by ICI 182,780. Neuropharmacology 2003, 44 (5), 584– 591, DOI: 10.1016/S0028-3908(03)00044-3[Crossref], [PubMed], [CAS], Google Scholar480https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXisFWns7o%253D&md5=d09ce0e8ed6011af13cfcd14d87e933fUncoupling of 5-HT1A receptors in the brain by estrogens: regional variations in antagonism by ICI 182,780Mize, A. L.; Young, L. J.; Alper, R. H.Neuropharmacology (2003), 44 (5), 584-591CODEN: NEPHBW; ISSN:0028-3908. (Elsevier Science Ltd.)Previously we have shown that 17β-estradiol (in vivo and in vitro) rapidly decreases the function of serotonin1A (5-HT1A) receptors, allowing us to hypothesize that 17β-estradiol accomplished this via activation of a membrane estrogen receptor. Hippocampus and frontal cortex obtained from ovariectomized rats were incubated with 17β-estradiol or bovine serum albumin (BSA)-estradiol in the presence or absence of the estrogen receptor (ER) antagonist ICI 182,780. Membranes were prepd. to measure R(+)8-OH-DPAT-stimulated [35S]GTPγS binding (a measure of 5-HT1A receptor coupling and function). In both hippocampus and frontal cortex, 17β-estradiol and BSA-estradiol (50 nM) decreased R(+)8-OH-DPAT-stimulated [35S]GTPγS binding. ICI 182,780 blocked the effect of both the estrogens in hippocampus, but only the effect of 17β-estradiol in frontal cortex. Due to the inability of ICI 182,780 to block the effects of BSA-estradiol in frontal cortex, similar expts. were performed using the selective estrogen receptor modulator tamoxifen as the agonist. Tamoxifen (100 nM and 1 μM) decreased R(+)8-OH-DPAT-stimulated [35S]GTPγS binding. ICI 182,780 (1 μM) blocked the ability of tamoxifen to decrease 5-HT1A receptor coupling in the hippocampus, but not in the frontal cortex. Taken together, these data support the existence of a pharmacol. distinct ER in hippocampus vs. frontal cortex that might be responsible for rapid uncoupling of 5-HT1A receptors.
- 474Cordey, M.; Pike, C. J. Neuroprotective Properties of Selective Estrogen Receptor Agonists in Cultured Neurons. Brain Res. 2005, 1045 (1–2), 217– 223, DOI: 10.1016/j.brainres.2005.03.032[Crossref], [PubMed], [CAS], Google Scholar481https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXks1ansbs%253D&md5=94da6a8dc25ddbd13b53ba9eda7f927bNeuroprotective properties of selective estrogen receptor agonists in cultured neuronsCordey, Myriam; Pike, Christian J.Brain Research (2005), 1045 (1-2), 217-223CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)To investigate the role of the estrogen receptor (ER) in mediating neuroprotection, the neuroprotective profiles of selective ER agonists for ERα and ERβ, propylpyrazole triol (PPT) and 2,3-bis(4-hydroxyphenyl) proprionitrile (DPN), resp., were compared to that of 17β-estradiol and 17α-estradiol in primary neuron cultures challenged by β-amyloid toxicity. All compds. were found to be neuroprotective in an ER-dependent manner. However, protein kinase C (PKC) inhibition completely blocked the protective effects of 17β-estradiol and 17α-estradiol and significantly attenuated PPT but not DPN neuroprotection. These data indicate that estrogen-mediated neuroprotection likely involves a variety of mechanisms and that protection due to PKC activation is more likely due to ERα compared to ERβ.
- 475Fitzpatrick, J. L.; Mize, A. L.; Wade, C. B.; Harris, J. A.; Shapiro, R. A.; Dorsa, D. M. Estrogen-Mediated Neuroprotection against β-Amyloid Toxicity Requires Expression of Estrogen Receptor α or β and Activation of the MAPK Pathway. J. Neurochem. 2002, 82 (3), 674– 682, DOI: 10.1046/j.1471-4159.2002.01000.x[Crossref], [PubMed], [CAS], Google Scholar482https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xmt1ejsbo%253D&md5=fd532c3b30517e4fec0923fad7a29157Estrogen-mediated neuroprotection against β-amyloid toxicity requires expression of estrogen receptor α or β and activation of the MAPK pathwayFitzpatrick, Jennifer L.; Mize, Amy L.; Wade, Christian B.; Harris, Julie A.; Shapiro, Robert A.; Dorsa, Daniel M.Journal of Neurochemistry (2002), 82 (3), 674-682CODEN: JONRA9; ISSN:0022-3042. (Blackwell Science Ltd.)It is well documented that estrogen can activate rapid signaling pathways in a variety of cell types. These non-classical effects of estrogen have been reported to be important for cell survival after exposure to a variety of neurotoxic insults. Since direct evidence of the ability of the estrogen receptors (ERs) α and/or β to mediate such responses is lacking, the hippocampal-derived cell line HT22 was stably transfected with either ERα (HTERα) or ERβ (HTERβ). In HTERα and HTERβ cells, but not untransfected cells, an increase in ERK2 phosphorylation was measured within 15 min of 17β-estradiol treatment. The ER antagonist ICI 182780 (1 μM) and the MEK inhibitor, PD 98059 (50 μM) blocked this increase in ERK2 phosphorylation. Treatment of HT22, HTERα and HTERβ cells with the β-amyloid peptide (25-35) (10 μM) resulted in a significant decrease in cell viability. Pretreatment for 15 min with 10 nM 17β-estradiol resulted in a 50% increase in the no. of living cells in HTERα and HTERβ cells, but not in HT22 cells. Finally, ICI 182 780 and PD 98059 prevented 17β-estradiol-mediated protection. This study demonstrates that both ERα and ERβ can couple to rapid signaling events that mediate estrogen-elicited neuroprotection.
- 476Tiwari-Woodruff, S.; Morales, L. B. J.; Lee, R.; Voskuhl, R. R. Differential Neuroprotective and Antiinflammatory Effects of Estrogen Receptor (ER)α and ERβ Ligand Treatment. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (37), 14813– 14818, DOI: 10.1073/pnas.0703783104[Crossref], [PubMed], [CAS], Google Scholar483https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2srjsFeksg%253D%253D&md5=59d26af3f0e8e6d12676c16f6d15b53aDifferential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatmentTiwari-Woodruff Seema; Morales Laurie Beth J; Lee Ruri; Voskuhl Rhonda RProceedings of the National Academy of Sciences of the United States of America (2007), 104 (37), 14813-8 ISSN:0027-8424.Treatment with either estradiol or an estrogen receptor (ER)alpha ligand has been shown to be both antiinflammatory and neuroprotective in a variety of neurological disease models, but whether neuroprotective effects could be observed in the absence of an antiinflammatory effect has remained unknown. Here, we have contrasted effects of treatment with an ERalpha vs. an ERbeta ligand in experimental autoimmune encephalomyelitis, the multiple sclerosis model with a known pathogenic role for both inflammation and neurodegeneration. Clinically, ERalpha ligand treatment abrogated disease at the onset and throughout the disease course. In contrast, ERbeta ligand treatment had no effect at disease onset but promoted recovery during the chronic phase of the disease. ERalpha ligand treatment was antiinflammatory in the systemic immune system, whereas ERbeta ligand treatment was not. Also, ERalpha ligand treatment reduced CNS inflammation, whereas ERbeta ligand treatment did not. Interestingly, treatment with either the ERalpha or the ERbeta ligand was neuroprotective, as evidenced by reduced demyelination and preservation of axon numbers in white matter, as well as decreased neuronal abnormalities in gray matter. Thus, by using the ERbeta selective ligand, we have dissociated the antiinflammatory effect from the neuroprotective effect of estrogen treatment and have shown that neuroprotective effects of estrogen treatment do not necessarily depend on antiinflammatory properties. Together, these findings suggest that ERbeta ligand treatment should be explored as a potential neuroprotective strategy in multiple sclerosis and other neurodegenerative diseases, particularly because estrogen-related toxicities such as breast and uterine cancer are mediated through ERalpha.
- 477Bourque, M.; Dluzen, D. E.; Di Paolo, T. Signaling Pathways Mediating the Neuroprotective Effects of Sex Steroids and SERMs in Parkinson’s Disease. Front. Neuroendocrinol 2012, 33 (2), 169– 178, DOI: 10.1016/j.yfrne.2012.02.003[Crossref], [PubMed], [CAS], Google Scholar484https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XksFehu7w%253D&md5=956c5c7e59cf122a446039e7a7bdb900Signaling pathways mediating the neuroprotective effects of sex steroids and SERMs in Parkinson's diseaseBourque, Melanie; Dluzen, Dean E.; Di Paolo, ThereseFrontiers in Neuroendocrinology (2012), 33 (2), 169-178CODEN: FNEDA7; ISSN:0091-3022. (Elsevier Inc.)A review. Studies with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinson's disease have shown the ability of 17β-estradiol to protect the nigrostriatal dopaminergic system. This paper reviews the signaling pathways mediating the neuroprotective effect of 17β-estradiol against MPTP-induced toxicity. The mechanisms of 17β-estradiol action implicate activation of signaling pathways such as the phosphatidylinositol-3 kinase/Akt and the mitogen-activated protein kinase pathways. 17β-estradiol signaling is complex and integrates multiple interactions with signaling mols. that act to potentiate a protective effect. 17β-Estradiol signaling is mediated via estrogen receptors, including GPER1, but others receptors, such as the IGF-1 receptor, are implicated in the neuroprotective effect. Glial and neuronal crosstalk is a crit. factor in the maintenance of dopamine neuronal survival and in the neuroprotective action of 17β-estradiol. Compds. that stimulate GPER1 such as selective estrogen receptor modulators and phytoestrogens show neuroprotective activity and are alternatives to 17β-estradiol.
- 478Zhao, L.; Brinton, R. D. Estrogen Receptor α and β Differentially Regulate Intracellular Ca2+ Dynamics Leading to ERK Phosphorylation and Estrogen Neuroprotection in Hippocampal Neurons. Brain Res. 2007, 1172, 48– 59, DOI: 10.1016/j.brainres.2007.06.092[Crossref], [PubMed], [CAS], Google Scholar485https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVOlsrjL&md5=9df2819c0ddcc5d968e1334a6176ef17Estrogen receptor α and β differentially regulate intracellular Ca2+ dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neuronsZhao, Liqin; Brinton, Roberta DiazBrain Research (2007), 1172 (), 48-59CODEN: BRREAP; ISSN:0006-8993. (Elsevier Ltd.)Our previous analyses indicated that both estrogen receptor (ER) subtypes, ERα and ERβ, contribute to estrogen neuroprotection (L. Zhao, et al., 2004). In the present study, we sought to det. the underlying mechanisms by which ERα and ERβ promote neuronal function, with a focus on neuroprotection, and whether these mechanisms are consistent with a classical nuclear or membrane ER-mediated response. Results of these analyses demonstrated that both the ERα-selective agonist, PPT (100 pM), and the ERβ-selective agonist, DPN (100 pM), were effective in dynamically but differentially regulating intracellular calcium (Ca2+) signaling in hippocampal neurons. Consistent with the direct measurement of neuroprotective outcomes (L. Zhao, et al., 2004), PPT and DPN exerted comparable efficacy in attenuating excitotoxic glutamate (200 μM)-induced intracellular Ca2+ rise. In contrast, DPN was more efficacious than PPT in potentiating a physiol. concn. of glutamate (25 μM)-induced intracellular Ca2+ rise in these neurons. Further analyses revealed that both PPT and DPN increased ERK phosphorylation, however, the temporal profile and magnitude of response were unique to each mol. The presence of the L-type Ca2+ channel inhibitor, nifedipine (10 μM), partially inhibited 17β-estradiol- and PPT-induced increase in phosphorylated ERK expression, whereas it induced a complete inhibition of DPN-induced increase in ERK phosphorylation. Addnl. neuroprotective expts. demonstrated that the MAPK inhibitor, PD 98059 (5 μM), partially blocked 17β-estradiol-induced promotion of neuronal survival against excitotoxic glutamate (200 μM)-induced neurotoxicity, whereas it completely blocked both PPT- and DPN-induced neuroprotection. The presence of the nuclear ER antagonist, ICI 182780 (1 μM), not only failed to block all 3 mol.-induced neuroprotection, but coadministration of ICI 182780 and each single mol. exerted a comparable or even greater neuroprotection. Taken together, as an expansion of our previous analyses, these data indicate that both ERα and ERβ contribute to neuronal mechanisms leading to estrogen promotion of neuronal function but with unique signaling profiles. Activation of ERβ and induction of intracellular Ca2+ influx via the L-type channels appears to be more closely assocd. with estrogen promotion of memory mechanisms. However, ERα and ERβ play an equivalently important role in mediating estrogen neuroprotection, and, which is dependent upon the activation of the MAPK signaling. Further, the present analyses suggest that sep. from a classical nuclear ER-mediated response, estrogen promotes neuronal survival likely through a non-nuclear cytoplasm or membrane-assocd. ER-mediated rapid signaling cascade.
- 479Yang, L.-C.; Zhang, Q.-G.; Zhou, C.-F.; Yang, F.; Zhang, Y.-D.; Wang, R.-M.; Brann, D. W. Extranuclear Estrogen Receptors Mediate the Neuroprotective Effects of Estrogen in the Rat Hippocampus. PLoS One 2010, 5 (5), e9851, DOI: 10.1371/journal.pone.0009851
- 480Long, J.; He, P.; Shen, Y.; Li, R. New Evidence of Mitochondria Dysfunction in the Female Alzheimer’s Disease Brain: Deficiency of Estrogen Receptor-β. J. Alzheimer's Dis. 2012, 30 (3), 545– 558, DOI: 10.3233/JAD-2012-120283[Crossref], [PubMed], [CAS], Google Scholar487https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotF2mtrg%253D&md5=4ca1f8aaf2b21d7ce1f58de0cd7f1874New Evidence of Mitochondria Dysfunction in the Female Alzheimer's Disease Brain: Deficiency of Estrogen Receptor-βLong, Jiangang; He, Ping; Shen, Yong; Li, RenaJournal of Alzheimer's Disease (2012), 30 (3), 545-558CODEN: JADIF9; ISSN:1387-2877. (IOS Press)Accumulating evidence suggests that mitochondria are important targets for the actions of estrogens and studies indicated that localization of estrogen receptor β (ERβ) in neuronal mitochondrial (mtERβ) might directly affect neuronal mitochondrial function in vitro. However, it is unknown what expression levels and how important mtERβ is in the human brain, particularly in a brain with Alzheimer's disease (AD). In the present study, using rapidly autopsied human brain tissue, we found that the frontal cortices of female AD patients exhibited significantly reduced mtERβ, along with reduced mitochondrial cytochrome C oxidase activity, and increased protein carbonylation compared to that in normal controls. The correlation between mtERβ expression and mitochondrial cytochrome C oxidase activity in the female human brain is significant. To understand the possible mechanisms of mtERβ in AD-related mitochondrial dysfunction, using ERβKO mice as a model, we found that lack of ERβ enhanced brain reactive oxygen species generation and reduced mitochondrial membrane potential under Aβ peptide insult compared to brain mitochondria from wild-type control mice. Our studies, for the first time, demonstrated neuronal mtERβ expression in the human brain and the deficiency of mtERβ in the female AD brain is assocd. with the dysfunction of mitochondria. Our results from ERβKO mice demonstrated that ERβ depletion-induced mitochondrial dysfunction is mediated through increasing reactive oxygen generation and redn. of mitochondria membrane potential. These results indicate that ERβ depletion impairs mitochondrial function in mice, and redn. of brain mtERβ may significantly contribute to the mitochondrial dysfunction involved in AD pathogenesis in women.
- 481Xu, H.; Gouras, G. K.; Greenfield, J. P.; Vincent, B.; Naslund, J.; Mazzarelli, L.; Fried, G.; Jovanovic, J. N.; Seeger, M.; Relkin, N. R.; Liao, F.; Checler, F.; Buxbaum, J. D.; Chait, B. T.; Thinakaran, G.; Sisodia, S. S.; Wang, R.; Greengard, P.; Gandy, S. Estrogen Reduces Neuronal Generation of Alzheimer β-Amyloid Peptides. Nat. Med. 1998, 4 (4), 447– 451, DOI: 10.1038/nm0498-447[Crossref], [PubMed], [CAS], Google Scholar488https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXisVeltLk%253D&md5=0e71f6c4a209a69314dc9d9fde19761bEstrogen reduces neuronal generation of Alzheimer β-amyloid peptidesXu, Huaxi; Gouras, Gunnar K.; Greenfield, Jeffrey P.; Vincent, Bruno; Naslund, Jan; Mazzarelli, Louis; Fried, Gabriel; Jovanovic, Jasmina N.; Seeger, Mary; Relkin, Norman R.; Liao, Fang; Checler, Frederic; Buxbaum, Joseph D.; Chait, Brian T.; Thinakaran, Gopal.; Sisodia, Sangram S.; Wang, Rong; Greengard, Paul; Gandy, SamNature Medicine (New York) (1998), 4 (4), 447-451CODEN: NAMEFI; ISSN:1078-8956. (Nature America)Alzheimer's disease (AD) is characterized by the accumulation of cerebral plaques composed of 40- and 42-amino acid β-amyloid (Aβ) peptides, and autosomal dominant forms of AD appear to cause disease by promoting brain Aβ accumulation. Recent studies indicate that postmenopausal estrogen replacement therapy may prevent or delay the onset of AD. Here we present evidence that physiol. levels of 17β-estradiol reduce the generation of Aβ by neuroblastoma cells and by primary cultures of rat, mouse and human embryonic cerebrocortical neurons. These results suggest a mechanism by which estrogen replacement therapy can delay or prevent AD.
- 482Watters, J. J.; Campbell, J. S.; Cunningham, M. J.; Krebs, E. G.; Dorsa, D. M. Rapid MembraneEffects of Steroids in Neuroblastoma Cells: Effects of Estrogen on Mitogen Activated Protein Kinase Signalling Cascade and c-Fos Immediate Early Gene Transcription. Endocrinology 1997, 138 (9), 4030– 4033, DOI: 10.1210/endo.138.9.5489[Crossref], [PubMed], [CAS], Google Scholar489https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlsFeisbk%253D&md5=280b42414d49c193d2ff67f4ae8eae03Rapid membrane effects of steroids in neuroblastoma cells: effects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcriptionWatters, Jyoti J.; Campbell, Jean S.; Cunningham, Matthew J.; Krebs, Edwin G.; Dorsa, Daniel M.Endocrinology (1997), 138 (9), 4030-4033CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)Rapid effects of steroid hormones have been obsd. in neuronal cells for many years. The authors show here, that in the human neuroblastoma cell line SK-N-SH, the membrane impermeable conjugated 17β-estradiol (E2BSA) activates mitogen activated protein kinase kinase (MAPKK or MEK) and induces the phosphorylation and activation of both ERK-1 and ERK-2 (mitogen activated protein kinase or MAPK). Addnl., E2BSA induces the transcription of a reporter gene construct driven by the promoter of the mouse c-fos proto-oncogene. The effects of this membrane impermeable estrogen on c-fos transcription are not inhibited by the estrogen receptor antagonists Tamoxifen or ICI 182,780, further excluding the involvement of the intracellular estrogen receptor. This is also illustrated by the observation that E2BSA does not activate estrogen response element (ERE) mediated transcription. This is the first report of rapid membrane effects of 17β-estradiol on growth factor related signaling pathways in neuronal cells, and indicates a potential mechanism by which 17β-estradiol might affect the expression of genes whose promoters do not contain EREs but are responsive to factors acting through other response elements such as AP-1 and SRE sites.
- 483Manthey, D.; Heck, S.; Engert, S.; Behl, C. Estrogen Induces a Rapid Secretion of Amyloid β Precursor Protein via the Mitogen-Activated Protein Kinase Pathway. Eur. J. Biochem. 2001, 268 (15), 4285– 4291, DOI: 10.1046/j.1432-1327.2001.02346.x[Crossref], [PubMed], [CAS], Google Scholar490https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlvF2gsLs%253D&md5=6614e55f62d4e0942d356c4a782f69ceEstrogen induces a rapid secretion of amyloid β precursor protein via the mitogen-activated protein kinase pathwayManthey, Dieter; Heck, Stefanie; Engert, Stefanie; Behl, ChristianEuropean Journal of Biochemistry (2001), 268 (15), 4285-4291CODEN: EJBCAI; ISSN:0014-2956. (Blackwell Science Ltd.)The female sex hormone estrogen (17β-estradiol; E2) may function as a neurohormone and has multiple neuromodulatory functions in the brain. Its potent neuroprotective activities can be dependent and independent of estrogen receptors (ERs). In addn., E2 influences the processing of the amyloid β precursor protein (APP), one central step in the pathogenesis of Alzheimer's disease. Here, the authors show that physiol. concns. of E2 very rapidly cause an increased release of secreted nonamyloidogenic APP (sAPPα) in mouse hippocampal HT22 and human neuroblastoma SK-N-MC cells and that this effect is mediated through E2 via the phosphorylation of extracellular-regulated kinase 1 and 2 (ERK1/2), prominent members of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, the authors show that the activation of MAPK-signaling pathway and the enhancement of the sAPP release is independent of ERs and could be induced by E2 to a similar extent in neuronal cells either lacking or overexpressing a functional ER.
- 484Li, R.; Shen, Y.; Yang, L.-B.; Lue, L.-F.; Finch, C.; Rogers, J. Estrogen Enhances Uptake of Amyloid β-Protein by Microglia Derived from the Human Cortex. J. Neurochem. 2000, 75 (4), 1447– 1454, DOI: 10.1046/j.1471-4159.2000.0751447.x[Crossref], [PubMed], [CAS], Google Scholar491https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmslGltr8%253D&md5=36e25def67aea99d0149b23feb12eec2Estrogen enhances uptake of amyloid β-protein by microglia derived from the human cortexLi, Rena; Shen, Yong; Yang, Li-Bang; Lue, Lih-Fen; Finch, Caleb; Rogers, JosephJournal of Neurochemistry (2000), 75 (4), 1447-1454CODEN: JONRA9; ISSN:0022-3042. (Lippincott Williams & Wilkins)In recent years, inflammatory mechanisms have been increasingly appreciated as important steps in the pathol. of Alzheimer's disease (AD). There are two pathol. defects in AD: chronic inflammation and impaired clearance of amyloid β-peptide (Aβ). In the periphery, estrogen both increases macrophage phagocytosis and has antiinflammatory effects. If estrogen had a similar effect in the CNS, it could reverse inflammatory defects in AD. Although microglia are a key component of the immune system and help clear Aβ deposits in the AD brain, little is known about the effects of estrogen on CNS microglia. Therefore, we sought to det. the relationship between estrogen treatment and internalization of Aβ by microglia by quantifying the internalization of aggregated Aβ by human cortical microglia. Aβ uptake was found to be dose- and time-dependent in cultured microglia. Increased Aβ uptake was obsd. at 1.5 and 24 h after addn. of aggregated Aβ (50, 100, or 1,000 nM Aβ), and this uptake was enhanced by pretreatment with estrogen. The expression of estrogen receptor (ER) β (ER-β) was also up-regulated by estrogen treatment. Cells cotreated with ICI 182,780, an ER antagonist, showed significantly reduced internalization of Aβ in cultured microglia. These results indicate that microglia express an ER-β but that the effect of estrogen on enhancing clearance of Aβ may be related to the receptor-independent action of estrogen or to nonclassical ER effects of estrogen. Thus, stimulation of the ER might contribute to the therapeutic action of estrogen in the treatment of AD.
- 485Harris-White, M. E.; Chu, T.; Miller, S. A.; Simmons, M.; Teter, B.; Nash, D.; Cole, G. M.; Frautschy, S. A. Estrogen (E2) and Glucocorticoid (Gc) Effects on Microglia and Aβ Clearance in Vitro and in Vivo. Neurochem. Int. 2001, 39 (5–6), 435– 448, DOI: 10.1016/S0197-0186(01)00051-1[Crossref], [PubMed], [CAS], Google Scholar492https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXntVymu7k%253D&md5=4523557643f257c23a69f4d449aca50cEstrogen (E2) and glucocorticoid (Gc) effects on microglia and Aβ clearance in vitro and in vivoHarris-White, M. E.; Chu, T.; Miller, S. A.; Simmons, M.; Teter, B.; Nash, D.; Cole, G. M.; Frautschy, S. A.Neurochemistry International (2001), 39 (5-6), 435-448CODEN: NEUIDS; ISSN:0197-0186. (Elsevier Science Ltd.)The accumulation of fibrillar aggregates of β-amyloid (Aβ) in alzheimer's disease (AD) brain is assocd. with chronic brain inflammation. Although activated microglia (μglia) can potentially clear toxic amyloid, chronic activation may lead to excessive prodn. of neurotoxins. Recent epidemiol. and clin. data have raised questions about the use of anti-inflammatory steroids (glucocorticoids, Gcs) and estrogens for treatment or prevention of AD. Since very little is known about steroid effects on μglial interactions with amyloid, we investigated the effects of the synthetic Gc dexamethasone (DXM) and 17β-estradiol (E2) in vitro in a murine μglial-like N9 cell line on toxin prodn. and intracellular Aβ accumulation. To det. whether the steroid alterations of Aβ uptake in vitro had relevance in vivo, we examd. the effects of these steroids on Aβ accumulation and μglial responses to Aβ infused into rat brain. Our in vitro data demonstrate for the first time that Gc dose-dependently enhanced μglial Aβ accumulation and support previous work showing that E2 enhances Aβ uptake. Despite both steroids enhancing uptake, degrdn. was impeded, particularly with Gcs. Distinct differences between the two steroids were obsd. in their effect on toxin prodn. and cell viability. Gc dose-dependently increased toxicity and potentiated Aβ induction of nitric oxide, while E2 promoted cell viability and inhibited Aβ induction of nitric oxide. The steroid enhancement of μglial uptake and impedence of degrdn. obsd. in vitro were consistent with observations from in vivo studies. In the brains of Aβ-infused rats, the μglial staining in entorhinal cortex layer 3, not assocd. with Aβ deposits was increased in response to Aβ infusion and this effect was blocked by feeding rats prednisolone. In contrast, E2 enhanced μglial staining in Aβ-infused rats. Aβ-immunoreactive (ir) deposits were quant. smaller, appeared denser, and were assocd. with robust μglial responses. Despite the fact that steroid produced a smaller more focal deposit, total extd. Aβ in cortical homogenate was elevated. Together, the in vivo and in vitro data support a role for steroids in plaque compaction. Our data are also consistent with the hypothesis that although E2 is less potent than Gc in impeding Aβ degrdn., long term exposure to both steroids could reduce Aβ clearance and clin. utility. These data showing Gc potentiation of Aβ-induced μglial toxins may help explain the lack of epidemiol. correlation for AD. The failure of both steroids to accelerate Aβ degrdn. may explain their lack of efficacy for treatment of AD.
- 486Bruce-Keller, A. J.; Keeling, J. L.; Keller, J. N.; Huang, F. F.; Camondola, S.; Mattson, M. P. Antiinflammatory Effects of Estrogen on Microglial Activation. Endocrinology 2000, 141 (10), 3646– 3656, DOI: 10.1210/endo.141.10.7693[Crossref], [PubMed], [CAS], Google Scholar493https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmvVGms7c%253D&md5=d39a25263a317cb4dc49b6a133944fc4Antiinflammatory effects of estrogen on microglial activationBruce-Keller, Annadora J.; Keeling, Jonathan L.; Keller, Jeffrey N.; Huang, Feng F.; Camondola, Simonetta; Mattson, Mark P.Endocrinology (2000), 141 (10), 3646-3656CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)In the present study the effects of 17β-estradiol on microglial activation are described. Estrogen replacement therapy has been assocd. with decreased severity of age-related neurodegenerative diseases such as Alzheimer's disease, and estrogens have potent immunosuppressive properties outside of the brain. To det. the role that microglial cells might play in estrogen-mediated neuroprotection, primary rat microglia and N9 microglial cell lines were treated with increasing doses of 17β-estradiol before or during immunostimulation by lipopolysaccharide, phorbol ester, or interferon-γ. Pretreatment with 17β-estradiol, but not 17α-estradiol or progesterone, dose dependently attenuated microglial superoxide release and phagocytic activity. Addnl., 17β-estradiol attenuated increases in inducible nitric oxide synthase protein expression, but did not alter nuclear factor-κB activation. The antiinflammatory effects of 17β-estradiol were blocked by the antiestrogen ICI 182,780. Addnl., 17β-estradiol induced rapid phosphorylation of the p42/p44 mitogen-activated protein kinase (MAP kinase), and the MAP kinase inhibitor PD 98059 blocked the antiinflammatory effects of 17β-estradiol. Overall, these results suggest that estrogen receptor-dependent activation of MAP kinase is involved in estrogen-mediated antiinflammatory pathways in microglial cells. These results describe a novel mechanism by which estrogen may attenuate the progression of neurodegenerative disease and suggest new pathways for therapeutic intervention in clin. settings.
- 487George, S.; Petit, G. H.; Gouras, G. K.; Brundin, P.; Olsson, R. Nonsteroidal Selective Androgen Receptor Modulators and Selective Estrogen Receptor β Agonists Moderate Cognitive Deficits and Amyloid-β Levels in a Mouse Model of Alzheimer’s Disease. ACS Chem. Neurosci. 2013, 4 (12), 1537– 1548, DOI: 10.1021/cn400133s[ACS Full Text], [CAS], Google Scholar494https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVWjsLfM&md5=e5ed323f02b34a16e96ed326e2b59f95Nonsteroidal Selective Androgen Receptor Modulators and Selective Estrogen Receptor β Agonists Moderate Cognitive Deficits and Amyloid-β Levels in a Mouse Model of Alzheimer's DiseaseGeorge, Sonia; Petit, Geraldine H.; Gouras, Gunnar K.; Brundin, Patrik; Olsson, RogerACS Chemical Neuroscience (2013), 4 (12), 1537-1548CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Decreases of the sex steroids, testosterone and estrogen, are assocd. with increased risk of Alzheimer's disease. Testosterone and estrogen supplementation improves cognitive deficits in animal models of Alzheimer's disease. Sex hormones play a role in the regulation of amyloid-β via induction of the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme. To mimic the effect of dihydrotestosterone (DHT), the authors administered a selective androgen receptor agonist, ACP-105, alone and in combination with the selective estrogen receptor β (ERβ) agonist AC-186 to male gonadectomized triple transgenic mice. The authors assessed long-term spatial memory in the Morris water maze, spontaneous locomotion, and anxiety-like behavior in the open field and in the elevated plus maze. The authors found that ACP-105 given alone decreases anxiety-like behavior. Furthermore, when ACP-105 is administered in combination with AC-186, they increase the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme and decrease amyloid-β levels in the brain as well as improve cognition. Interestingly, the androgen receptor level in the brain was increased by chronic treatment with the same combination treatment, ACP-105 and AC-186, not seen with DHT or ACP-105 alone. Based on these results, the beneficial effect of the selective ERβ agonist as a potential therapeutic for Alzheimer's disease warrants further investigation.
- 488Yue, X.; Lu, M.; Lancaster, T.; Cao, P.; Honda, S. I.; Staufenbiel, M.; Harada, N.; Zhong, Z.; Shen, Y.; Li, R. Brain Estrogen Deficiency Accelerates Aβ Plaque Formation in an Alzheimer’s Disease Animal Model. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (52), 19198– 19203, DOI: 10.1073/pnas.0505203102[Crossref], [PubMed], [CAS], Google Scholar495https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XivV2ntQ%253D%253D&md5=32b673dfb677f2dc03b94f8b335c5f6dBrain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal modelYue, Xu; Lu, Melissa; Lancaster, Techie; Cao, Phillip; Honda, Shin-Ichiro; Staufenbiel, Matthias; Harada, Nobuhiro; Zhong, Zhenyu; Shen, Yong; Li, RenaProceedings of the National Academy of Sciences of the United States of America (2005), 102 (52), 19198-19203CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Much evidence indicates that women have a higher risk of developing Alzheimer's disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor. In rapidly acquired postmortem brains from women with AD, we found greatly reduced estrogen levels compared with those from age- and gender-matched normal control subjects; AD and control subjects had comparably low levels of serum estrogen. We examd. the onset and severity of AD pathol. assocd. with estrogen depletion by using a gene-based approach, by crossing the estrogen-synthesizing enzyme aromatase gene knockout mice with APP23 transgenic mice, a mouse model of AD, to produce estrogen-deficient APP23 mice. Compared with APP23 transgenic control mice, estrogen-deficient APP23 mice exhibited greatly reduced brain estrogen and early-onset and increased β amyloid peptide (Aβ) deposition. These mice also exhibited increased Aβ prodn., and microglia cultures prepd. from the brains of these mice were impaired in Aβ clearance/degrdn. In contrast, ovariectomized APP23 mice exhibited plaque pathol. similar to that obsd. in the APP23 transgenic control mice. Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathol.
- 489Tanzi, R. E.; Moir, R. D.; Wagner, S. L. Clearance of Alzheimer’s Aβ Peptide: The Many Roads to Perdition. Neuron 2004, 43, 605– 608, DOI: 10.1016/j.neuron.2004.08.024[Crossref], [PubMed], [CAS], Google Scholar496https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXns1ymsrg%253D&md5=57e1c038b256c85240463ca9b14afcadClearance of Alzheimer's Aβ peptide: The many roads to perditionTanzi, R. E.; Moir, R. D.; Wagner, S. L.Neuron (2004), 43 (5), 605-608CODEN: NERNET; ISSN:0896-6273. (Cell Press)A review. The amyloid hypothesis of Alzheimer's disease (AD) maintains that the accumulation of the amyloid β protein (Aβ) is a crit. event in disease pathogenesis. A great deal of both academic and com. research has focused on the mechanisms by which Aβ is generated. However, investigations into the mechanisms underlying Aβ clearance have blossomed over the last several years. This minireview will summarize pathways involved in the removal of cerebral Aβ, including enzymic degrdn. and receptor-mediated efflux out of the brain.
- 490Wei, Y.; Zhou, J.; Wu, J.; Huang, J. ERβ Promotes Aβ Degradation via the Modulation of Autophagy. Cell Death Dis. 2019, 10 (8), 565, DOI: 10.1038/s41419-019-1786-8[Crossref], [PubMed], [CAS], Google Scholar497https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MzpvFygtw%253D%253D&md5=d6dd608f094f1834fcd76478bdd7ab2dERβ promotes Aβ degradation via the modulation of autophagyWei Yong; Zhou Jiawei; Wu Jun; Huang JianCell death & disease (2019), 10 (8), 565 ISSN:.Alzheimer's Disease (AD) is the most common neurodegenerative disorder in the elderly. Beta-amyloid (Aβ) peptide accumulation is considered as a primary cause of AD pathogenesis, with defective autophagy in patients' brains. Enhanced autophagic activity has been reported to promote Aβ clearance in vitro and in vivo models. Meanwhile, there is growing evidence that estrogen receptor β (ERβ) is a viable therapeutic target that can ameliorate the pathological features associated with AD. Very little is known about the detailed molecular mechanisms underlying the relationship between ERβ, autophagy, and Aβ degradation in AD. This study aims to uncover whether ERβ participates in autophagy and promotes extracellular Aβ1-42 degradation through the autophagy-lysosome system. Here we find that overexpression of ERβ caused autophagic activation as seen by increased microtubule-associated protein 1 light chain 3-II (LC3-II), SQSTM1 (sequestosome 1) degradation, LC3 punctate distribution, autophagosome, and autolysosome accumulation. In addition, we show that ERβ could induce autophagy through direct protein-protein interaction with ATG7 (E1-like enzyme). Furthermore, ERβ-mediated decrease in Aβ1-42 was blocked by the autophagy inhibitor chloroquine (CQ) in SH-SY5Y cells and the HEK293T (AβPPsw) model. Aβ1-42 or CQ induced cytotoxicity was restored by a selective ERβ activator diarylpropionitrile (DPN). Collectively, these data indicate that overexpression of ERβ exerts a neuroprotective effect through interacting with ATG7 protein and further enhances autophagy-lysosomal activity for Aβ1-42 clearance at the cellular level.
- 491Hayes, M. T. Parkinson’s Disease and Parkinsonism. American Journal of Medicine 2019, 132 (7), 802– 807, DOI: 10.1016/j.amjmed.2019.03.001.[Crossref], [PubMed], [CAS], Google Scholar498https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cbmtVartA%253D%253D&md5=31c8a0bb44baf180225ca9aed18c4a18Parkinson's Disease and ParkinsonismHayes Michael TThe American journal of medicine (2019), 132 (7), 802-807 ISSN:.Parkinson's disease is a progressive neurodegenerative disease characterized by tremor and bradykinesia and is a common neurologic ailment. Male sex and advancing age are independent risk factors and, as the population ages, is taking an increasing toll on productivity and medical resources. There are a number of other extrapyramidal conditions that can make the diagnosis challenging. Unlike other neurodegenerative diseases, idiopathic Parkinson's disease has effective treatments that mitigate symptoms. Medications can improve day-to-day function and, in cases where medication does not give a sustained benefit or has significant side effects, treatments like deep brain stimulation result in improved quality of life.
- 492Popat, R. A.; Van Den Eeden, S. K.; Tanner, C. M.; McGuire, V.; Bernstein, A. L.; Bloch, D. A.; Leimpeter, A.; Nelson, L. M. Effect of Reproductive Factors and Postmenopausal Hormone Use on the Risk of Parkinson Disease. Neurology 2005, 65 (3), 383– 390, DOI: 10.1212/01.wnl.0000171344.87802.94[Crossref], [PubMed], [CAS], Google Scholar499https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmsVyjtLY%253D&md5=4e8bdd89034e9ea435f588a3d86c2c9cEffect of reproductive factors and postmenopausal hormone use on the risk of Parkinson diseasePopat, R. A.; Van Den Eeden, S. K.; Tanner, C. M.; McGuire, V.; Bernstein, A. L.; Bloch, D. A.; Leimpeter, A.; Nelson, L. M.Neurology (2005), 65 (3), 383-390CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: Parkinson disease (PD) is less common in women possibly because of hormonal or reproductive influences. The objective of this study was to evaluate the assocns. of reproductive factors and postmenopausal hormone use with the risk of PD among postmenopausal women. Methods: Incident cases and randomly selected age-matched controls who were members of the Kaiser Permanente Medical Care Program (KPMCP) of Northern California participated in the study conducted during the years 1994 to 1995. Statistical analyses were carried out using logistic regression. Results: The assocn. of postmenopausal hormone use with PD risk depended on the type of menopause. Among women with history of a hysterectomy with or without an oophorectomy, estrogen use alone was assocd. with a 2.6-fold increased risk (adjusted odds ratio (OR) 2.6, 95% CI: 1.1 to 6.1) and significant trends in the risk of PD were obsd. with increasing duration of estrogen use, but disease risk was not influenced by recency of use. In contrast, among women with natural menopause, no increased risk of PD was obsd. with hormone use (estrogen alone or a combined estrogen-progestin regimen). Early age at final menstrual period (44 years or younger) was assocd. with redn. in risk (adjusted OR 0.5, 95% CI: 0.3 to 1.0). Age at menarche and parity were not assocd. with the risk of PD. Conclusion: Postmenopausal use of estrogen alone may increase the risk of Parkinson disease (PD) among women with a hysterectomy. Among women with natural menopause for whom the usual treatment is combined estrogen-progestin therapy, no increased risk of PD was obsd.
- 493Wang, P.; Li, J.; Qiu, S.; Wen, H.; Du, J. Hormone Replacement Therapy and Parkinson’s Disease Risk in Women: A Meta-Analysis of 14 Observational Studies. Neuropsychiatr. Dis. Treat. 2015, 11, 59– 66, DOI: 10.2147/NDT.S69918[Crossref], [PubMed], [CAS], Google Scholar500https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mrjtlequw%253D%253D&md5=68aef7f78d6f85cee0571952bcdfbee0Hormone replacement therapy and Parkinson's disease risk in women: a meta-analysis of 14 observational studiesWang Peifu; Li Jilai; Qiu Shi; Wen Honfeng; Du JichenNeuropsychiatric disease and treatment (2015), 11 (), 59-66 ISSN:1176-6328.BACKGROUND AND PURPOSE: Published data on the relationship of hormone replacement therapy (HRT) with Parkinson's disease (PD) were inconclusive. Thus, a systematic meta-analysis of observational studies was performed to clarify this topic. METHODS: The databases of PubMed and EMBASE were searched for case-control or cohort studies published up till June 2, 2014. Meta-analysis of the relative risks (RRs) with 95% confidence intervals (CIs) was estimated using random-effects models. RESULTS: A final total of ten case-control and four cohort studies were included in our meta-analysis. The overall combined RR of PD for ever users versus never users of HRT was 1.00 (95% CI: 0.84-1.20). Limited to those subjects who only use estrogen, a similar trend was detected (RR: 0.95, 95% CI: 0.69-1.30). In the subgroup analysis by study design, no significant association was observed in case-control studies (RR: 0.79, 95% CI: 0.62-1.02), whereas a positive association was found in cohort studies (RR: 1.24, 95% CI: 1.10-1.40). In further analysis according to study quality, an inverse association was found in the low-quality group (RR: 0.58, 95% CI: 0.40-0.82), whereas a positive association was found in the high-quality group (RR: 1.16, 95% CI: 1.02-1.31). CONCLUSION: In summary, our results of meta-analysis do not support a protective role of HRT in female PD development.
- 494Currie, L. J.; Harrison, M. B.; Trugman, J. M.; Bennett, J. P.; Wooten, G. F. Postmenopausal Estrogen Use Affects Risk for Parkinson Disease. Arch. Neurol. 2004, 61 (6), 886– 888, DOI: 10.1001/archneur.61.6.886[Crossref], [PubMed], [CAS], Google Scholar501https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2czgvVSlsA%253D%253D&md5=767a64537757741e871b0e657af47625Postmenopausal estrogen use affects risk for Parkinson diseaseCurrie Lillian J; Harrison Madaline B; Trugman Joel M; Bennett James P; Wooten G FrederickArchives of neurology (2004), 61 (6), 886-8 ISSN:0003-9942.BACKGROUND: Although estrogen therapy has been associated with improved cognitive functioning, a reduced risk of dementia in women with Parkinson disease (PD), and a decreased risk of Alzheimer disease, estrogen therapy has not affected the risk of PD per se. OBJECTIVE: To determine whether postmenopausal women with PD differed from control subjects with regard to estrogen exposure.Design, Setting, and Patients A case-control design was used, abstracting questionnaire data obtained via interview from 133 female PD cases and 128 female controls during routine outpatient clinic visits in 1999 at a mid-Atlantic tertiary care referral center. There were 140 subjects (68 PD cases and 72 controls) who met the inclusion criteria. Main Outcome Measure Use of postmenopausal estrogen therapy. RESULTS: More women in the control group than in the PD group took postmenopausal estrogen (36 [50%] of 72 women vs 17 [25%] of 68 women; P<.003), and women who had taken postmenopausal estrogen were less likely to develop PD than those who had not (odds ratio, 0.40 [95% confidence interval, 0.19-0.84]; P<.02). Among PD cases only, postmenopausal estrogen use was not associated with age of onset. CONCLUSION: Postmenopausal estrogen therapy may be associated with a reduced risk of PD in women.
- 495Bourque, M.; Morissette, M.; Di Paolo, T. Repurposing Sex Steroids and Related Drugs as Potential Treatment for Parkinson’s Disease. Neuropharmacology 2019, 147, 37– 54[Crossref], [PubMed], [CAS], Google Scholar502https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXptlyrs7g%253D&md5=c84953b16b20c814ba37776792e3abc1Repurposing sex steroids and related drugs as potential treatment for Parkinson's diseaseBourque, Melanie; Morissette, Marc; Di Paolo, ThereseNeuropharmacology (2019), 147 (), 37-54CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)Parkinson's disease (PD) is a neurodegenerative disorder for which a greater prevalence and incidence is described in men. This suggests a protective effect of sex hormones in the brain. Therefore, steroids and drugs to treat endocrine conditions could have addnl. application for PD. Here, we review the protective effect of sex hormones, particularly estrogens, progesterone, androgens and dehydroepiandrosterone, in animal models of PD and also in human studies. Data also support that drugs affecting estrogen neurotransmission such as selective estrogen receptor modulators or affecting steroid metab. with 5α-reductase inhibitors could be repositioned for treatment of PD. Sex steroids are also modulator of neurotransmission, thus they could repurposed to treat PD motor symptoms and to modulate the response to PD medication. No drug is yet available to limit PD progression. PD is a complex disease implicating multiple pathol. processes and a therapeutic strategy using drugs with several mechanisms of action, such as sex steroids and endocrine drugs are interesting repositioning options for symptomatic treatment and disease-modifying activity for PD.
- 496Blanchet, P. J.; Fang, J.; Hyland, K.; Arnold, L. A.; Mouradian, M. M.; Chase, T. N. Short-Term Effects of High-Dose 17β-Estradiol in Postmenopausal PD Patients: A Crossover Study. Neurology 1999, 53 (1), 91– 95, DOI: 10.1212/WNL.53.1.91[Crossref], [PubMed], [CAS], Google Scholar503https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXkvFCktrY%253D&md5=7f31de833c5c5a6ab5035d6186560d71Short-term effects of high-dose 17β-estradiol in postmenopausal PD patients: a crossover studyBlanchet, P. J.; Fang, J.; Hyland, K.; Arnold, L. A.; Mouradian, M. M.; Chase, T. N.Neurology (1999), 53 (1), 91-95CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)A double-blind, placebo-controlled, 2-arm crossover study of high-dose transdermal 17β-estradiol was conducted in 8 postmenopausal women with mild to moderate Parkinson's disease (PD), all but one of whom exhibited levodopa-induced dyskinesias. The patients were randomized initially to receive either hormonal treatment or placebo for 2 wk, followed by a 2-wk washout period, and then another 2-wk crossover treatment period. Active treatment employed 4 skin patches, each releasing 0.1 mg estradiol daily, replaced every 2-3 days. After 10 days of treatment a redn. was obsd. in the antiparkinsonian threshold dose of i.v. levodopa. The mean duration and magnitude of the antiparkinsonian response to threshold or high doses of levodopa were unchanged, and dyskinesia scores were unaltered during 17β-estradiol treatment compared with placebo. No worsening of "on" time or motor ratings with estrogen treatment was documented. Thus, 17β-estradiol appears to display a slight prodopaminergic (or antiparkinsonian) effect without consistently altering dyskinesias. Std. postmenopausal replacement therapy with transdermal 17β-estradiol is likely to be well tolerated by many female parkinsonian patients.
- 497Strijks, E.; Kremer, J. A. M.; Horstink, M. W. I. M. Effects of Female Sex Steroids on Parkinson’s Disease in Postmenopausal Women. Clin. Neuropharmacol. 1999, 22 (2), 93– 97, DOI: 10.1097/00002826-199903000-00005[Crossref], [PubMed], [CAS], Google Scholar504https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXisFajtLs%253D&md5=a73038cd8fab8adede3a2d44a85d111eEffects of female sex steroids on Parkinson's disease in postmenopausal womenStrijks, Elma; Kremer, Jan A. M.; Horstink, Martin W. I. M.Clinical Neuropharmacology (1999), 22 (2), 93-97CODEN: CLNEDB; ISSN:0362-5664. (Lippincott Williams & Wilkins)There are conflicting reports about estrogen modulating the activity of nigrostriatal dopaminergic neurons. Furthermore, modulation may be influenced by progesterone levels. Therefore, the clin. effects of sex steroids on parkinsonian symptoms in postmenopausal women with Parkinson's disease (PD) were analyzed in the present study. Patients (n = 12) were under the age of 80, able to perform the motor function tests, and showed no contraindications for estrogen suppletion. Motor function was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) and a patient interview on subjective changes. In a placebo-controlled, randomized, double-blind trial lasting 8 wk, no significant dopaminergic effect of estradiol (E2) could be demonstrated, whereas in an open trial phase lasting 2 wk, progesterone seemed to have an antidopaminergic effect. Several mechanisms are discussed that can account for the fact that we found no effect of E2 on motor functioning in our patients with PD.
- 498Dluzen, D. E.; McDermott, J. L.; Anderson, L. I. Tamoxifen Eliminates Estrogen’s Neuroprotective Effect upon MPTP-Induced Neurotoxicity of the Nigrostriatal Dopaminergic System. Neurotoxic. Res. 2001, 3 (3), 291– 300, DOI: 10.1007/BF03033268[Crossref], [PubMed], [CAS], Google Scholar505https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXotVeku7g%253D&md5=2c6bfa6c46a6c362b7769c6e4b8d153bTamoxifen eliminates estrogen's neuroprotective effect upon MPTP-induced neurotoxicity of the nigrostriatal dopaminergic systemDluzen, Dean E.; McDermott, Janet L.; Anderson, Linda I.Neurotoxicity Research (2001), 3 (3), 291-300CODEN: NURRFI; ISSN:1029-8428. (Harwood Academic Publishers)The capacity for 17-α and 17-β estradiol to modulate MPTP-induced neurotoxicity of the nigrostriatal dopaminergic system and potential antagonism of this modulation by the anti-estrogen, tamoxifen, were evaluated. Treatment of retired breeder ovariectomized C57/BI mice with 17-β estradiol diminished the amt. of striatal dopamine redn. resulting from MPTP treatment with striatal dopamine concns. of these 17-β estradiol treated mice failing to differ significantly from vehicle treated controls. A combined administration of 17-β estradiol with tamoxifen abolished this neuroprotective effect of estrogen as striatal dopamine concns. of this group were significantly lower than vehicle treated controls. Results of 17-α estradiol were less effective since striatal dopamine concns. of these mice following MPTP treatment were significantly decreased as compared with vehicle controls. In contrast to the nigrostriatal dopaminergic system, no statistically significant effects of these treatments were obsd. upon olfactory bulb dopamine concns. Taken together, these results show that 17-β, but not an equiv. concn. of 17-α, estradiol was effective in decreasing striatal dopamine neurotoxicity to MPTP. This effect of 17-β estradiol was abolished by tamoxifen. These data have important implications regarding the mechanisms of estrogen-tamoxifen interactions within the nigrostriatal dopaminergic system as well as for clin. applications of tamoxifen within pre-menopausal women.
- 499Morissette, M.; Sweidi, S. Al; Callier, S.; Di Paolo, T. Estrogen and SERM Neuroprotection in Animal Models of Parkinson’s Disease. Mol. Cell. Endocrinol. 2008, 290 (1–2), 60– 69, DOI: 10.1016/j.mce.2008.04.008[Crossref], [PubMed], [CAS], Google Scholar506https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpsValt7Y%253D&md5=909079982647aa992148a072b8fdb1deEstrogen and SERM neuroprotection in animal models of Parkinson's diseaseMorissette, Marc; Al Sweidi, Sara; Callier, Sophie; Di Paolo, ThereseMolecular and Cellular Endocrinology (2008), 290 (1-2), 60-69CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ireland Ltd.)A review. A higher prevalence and incidence of Parkinson disease (PD) is obsd. in men and beneficial motor effects of estrogens are obsd. in parkinsonian women. Lesion of the dopamine (DA) nigrostriatal pathway in animals with 1-Me 4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) provides a model of PD and this is based on its use in humans as side-product of a drug abuse. Presently treatment of PD is mainly symptomatic. The MPTP mouse is used to study the neuroprotective roles of estrogenic drugs on the DA system. Estrogens, but not androgens, are active neuroprotectants as well as progesterone and dehydroepiandrosterone. An estrogen receptor agonist PPT and the selective estrogen receptor modulator raloxifene are also neuroprotective. Striatal DA neurons of estrogen receptor alpha knockout mice are more susceptible to MPTP toxicity than wild-type mice and neuroprotection by estradiol is assocd. with the activation of the PI3-K pathway involving Akt, GSK3β, Bcl2 and BAD.
- 500Baraka, A. M.; Korish, A. A.; Soliman, G. A.; Kamal, H. The Possible Role of Estrogen and Selective Estrogen Receptor Modulators in a Rat Model of Parkinson’s Disease. Life Sci. 2011, 88 (19–20), 879– 885, DOI: 10.1016/j.lfs.2011.03.010[Crossref], [PubMed], [CAS], Google Scholar507https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsFShurk%253D&md5=eac948c5383fbf5eb0a44efffbb54030The possible role of estrogen and selective estrogen receptor modulators in a rat model of Parkinson's diseaseBaraka, Azza M.; Korish, Aida A.; Soliman, Gehan A.; Kamal, HananLife Sciences (2011), 88 (19-20), 879-885CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)The aim of the present study was to assess and compare the effect of 17β-estradiol and two different selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, as well as a selective estrogen receptor alpha agonist, propyl-pyrazole-triol (PPT) and a selective estrogen receptor beta agonist, diarylpropionitrile (DPN), on behavioral and biochem. alterations in 6-hydroxydopamine (6-OHDA)-induced nigral dopaminergic cell death in rats. 80 Female Wister rats were used. Animals were divided into eight equal groups: Group I; Sham operated, Group II; subjected to ovariectomy (OVX), Group III; OVX rats received striatal injection of 6-OHDA, Groups IV-VIII; OVX rats received striatal injection of 6-OHDA and were injected daily with 17β-estradiol, tamoxifen, raloxifene, PPT and DPN resp. for 5 days before 6-OHDA and continued for further 2 wk. Results showed that striatal injection of 6-OHDA produced significant behavioral alteration suggestive of PD, together with significant decrease in striatal dopamine, homovanillic acid (HVA) and 3,4-dihydroxyphenyl acetic acid (DOPAC) concns. 6-OHDA-induced nigral dopaminergic cell death was characterized by oxidative stress, evidenced by significant decrease in striatal glutathione peroxidase activity, as well as apoptosis, evidenced by significant increase in nigral caspase-3 activity. Treatment with 17β-estradiol, raloxifene, PPT, but neither tamoxifen nor DPN, resulted in significant amelioration of the behavioral and biochem. alterations induced by 6-OHDA. These findings suggest that estrogen and some SERMs having estrogenic agonist activity in the brain, like raloxifene, might exert beneficial effect in PD.
- 501McFarland, K.; Price, D. L.; Davis, C. N.; Ma, J.-N.; Bonhaus, D. W.; Burstein, E. S.; Olsson, R. AC-186, a Selective Nonsteroidal Estrogen Receptor β Agonist, Shows Gender Specific Neuroprotection in a Parkinson’s Disease Rat Model. ACS Chem. Neurosci. 2013, 4 (9), 1249– 1255, DOI: 10.1021/cn400132u[ACS Full Text], [CAS], Google Scholar508https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFOqu7rF&md5=52bc40346a15593c280019ae2c8b2600AC-186, a Selective Nonsteroidal Estrogen Receptor β Agonist, Shows Gender Specific Neuroprotection in a Parkinson's Disease Rat ModelMcFarland, Krista; Price, Diana L.; Davis, Christopher N.; Ma, Jian-Nong; Bonhaus, Douglas W.; Burstein, Ethan S.; Olsson, RogerACS Chemical Neuroscience (2013), 4 (9), 1249-1255CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Drugs that selectively activate estrogen receptor β (ERβ) are potentially safer than the nonselective estrogens currently used in hormonal replacement treatments that activate both ERβ and ERα. The selective ERβ agonist AC-186 was evaluated in a rat model of Parkinson's disease induced through bilateral 6-hydroxydopamine lesions of the substantia nigra. In this model, AC-186 prevented motor, cognitive, and sensorimotor gating deficits and mitigated the loss of dopamine neurons in the substantia nigra, in males, but not in females. Furthermore, in male rats, 17β-estradiol, which activates ERβ and ERα with equal potency, did not show the same neuroprotective benefits as AC-186. Hence, in addn. to a beneficial safety profile for use in both males and females, a selective ERβ agonist has a differentiated pharmacol. profile compared to 17β-estradiol in males.
- 502Sierra, A.; Gottfried-Blackmore, A.; Milner, T. A.; McEwen, B. S.; Bulloch, K. Steroid Hormone Receptor Expression and Function in Microglia. Glia 2008, 56 (6), 659– 674, DOI: 10.1002/glia.20644[Crossref], [PubMed], [CAS], Google Scholar509https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c7os12nsA%253D%253D&md5=2537a6e7d539d13d0c282566dc0cfd3fSteroid hormone receptor expression and function in microgliaSierra Amanda; Gottfried-Blackmore Andres; Milner Teresa A; McEwen Bruce S; Bulloch KarenGlia (2008), 56 (6), 659-74 ISSN:0894-1491.Steroid hormones such as glucocorticoids and estrogens are well-known regulators of peripheral immune responses and also show anti-inflammatory properties in the brain. However, the expression of steroid hormone receptors in microglia, the pivotal immune cell that coordinates the brain inflammatory response, is still controversial. Here we use real time RT-PCR to show that microglia, isolated from adult fms-EGFP mice by FACS, express glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and estrogen receptor alpha (ERalpha). GR was the most abundant steroid hormone receptor transcript in microglia. The presence of GR and ERalpha immunoreactivity was further confirmed in vivo at the ultrastructural level. To understand the role of steroid hormone receptors during the inflammation process, we evaluated the expression of steroid hormone receptors after inflammatory challenge and found a significant down-regulation of GR, MR, and ERalpha in microglia. Finally, we tested the immunomodulatory properties of estrogens and glucocorticoids. Estradiol benzoate did not have any significant impact on the inflammatory profile of ex vivo sorted microglia, either in resting conditions or after challenge. Furthermore, corticosterone was a more consistent anti-inflammatory agent than 17beta-estradiol in vitro. Our results support the hypothesis that adult microglia are a direct target of steroid hormones and that glucocorticoids, through the predominant expression of GR and MR, are the primary steroid hormone regulators of microglial inflammatory activity. The down-regulation of steroid hormone receptors after LPS challenge may serve as a prerequisite to suppressing the anti-inflammatory actions of endogenous steroid hormones on the immune system, and contribute to a sustained activation of microglia.
- 503Barreto, G.; Santos-Galindo, M.; Diz-Chaves, Y.; Pernía, O.; Carrero, P.; Azcoitia, I.; Garcia-Segura, L. M. Selective Estrogen Receptor Modulators Decrease Reactive Astrogliosis in the Injured Brain: Effects of Aging and Prolonged Depletion of Ovarian Hormones. Endocrinology 2009, 150 (11), 5010– 5015, DOI: 10.1210/en.2009-0352[Crossref], [PubMed], [CAS], Google Scholar510https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVCht7bJ&md5=2a0b63f7371e51901b11082774430ffdSelective estrogen receptor modulators decrease reactive astrogliosis in the injured brain: effects of aging and prolonged depletion of ovarian hormonesBarreto, George; Santos-Galindo, Maria; Diz-Chaves, Yolanda; Pernia, Olga; Carrero, Paloma; Azcoitia, Inigo; Garcia-Segura, Luis M.Endocrinology (2009), 150 (11), 5010-5015CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)After brain injury, astrocytes acquire a reactive phenotype characterized by a series of morphol. and mol. modifications, including the expression of the cytoskeletal protein vimentin. Previous studies have shown that estradiol down-regulates reactive astrogliosis. In this study we assessed whether raloxifene and tamoxifen, two selective estrogen receptor modulators, have effects similar to estradiol in astrocytes. We also assessed whether aging and the timing of estrogenic therapy after ovariectomy influence the action of the estrogenic compds. Four groups of animals were studied: (1) young rats, ovariectomized at 2 mo of age; (2) middle-aged rats, ovariectomized at 8 mo of age; (3) aged rats, ovariectomized at 18 mo of age; and (4) aged rats, ovariectomized at 2 mo and sham operated at 18 mo of age. Fifteen days after ovariectomy or sham surgery, animals received a stab wound brain injury and the treatment with the estrogenic compds. The no. of vimentin-immunoreactive astrocytes after injury was significantly higher in the hippocampus of aged rats after a long-term ovariectomy compared with aged animals after a short-term ovariectomy and middle-aged rats. In addn., reactive astrocytes were more numerous in the two groups of aged animals than in young animals. Despite these differences, the estrogenic compds. reduced reactive astrogliosis in all animal groups. These findings indicate that estradiol, raloxifene, and tamoxifen are potential candidates for the control of astrogliosis in young and older individuals and after a prolonged depletion of ovarian hormones.
- 504Maglione, A.; Rolla, S.; De Mercanti, S. F.; Cutrupi, S.; Clerico, M. The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View. Cells 2019, 8 (10), 1280, DOI: 10.3390/cells8101280[Crossref], [CAS], Google Scholar511https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnsFOktrw%253D&md5=e8a0b2188da433ff60b032b46d705c8dThe adaptive immune system in multiple sclerosis: an estrogen-mediated point of viewMaglione, Alessandro; Rolla, Simona; De Mercanti, Stefania Federica; Cutrupi, Santina; Clerico, MarinellaCells (2019), 8 (10), 1280CODEN: CELLC6; ISSN:2073-4409. (MDPI AG)Multiple sclerosis (MS) is a chronic central nervous system inflammatory disease that leads to demyelination and neurodegeneration. The third trimester of pregnancy, which is characterized by high levels of estrogens, has been shown to be assocd. with reduced relapse rates compared with the rates before pregnancy. These effects could be related to the anti-inflammatory properties of estrogens, which orchestrate the reshuffling of the immune system toward immunotolerance to allow for fetal growth. The action of these hormones is mediated by the transcriptional regulation activity of estrogen receptors (ERs). Estrogen levels and ER expression define a specific balance of immune cell types. In this review, we explore the role of estradiol (E2) and ERs in the adaptive immune system, with a focus on estrogen-mediated cellular, mol., and epigenetic mechanisms related to immune tolerance and neuroprotection in MS. The epigenome dynamics of immune systems are described as key mol. mechanisms that act on the regulation of immune cell identity. This is a completely unexplored field, suggesting a future path for more extensive research on estrogen-induced coregulatory complexes and mol. circuitry as targets for therapeutics in MS.
- 505Villa, A.; Vegeto, E.; Poletti, A.; Maggi, A. Estrogens, Neuroinflammation, and Neurodegeneration. Endocrine Reviews 2016, 37 (4), 372– 402, DOI: 10.1210/er.2016-1007[Crossref], [PubMed], [CAS], Google Scholar512https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXkt1ykur0%253D&md5=dd42df0f5162ee810532218379d8fba2Estrogens, neuroinflammation, and neurodegenerationVilla, Alessandro; Vegeto, Elisabetta; Poletti, Angelo; Maggi, AdrianaEndocrine Reviews (2016), 37 (4), 372-402CODEN: ERVIDP; ISSN:1945-7189. (Endocrine Society)Inflammatory activation of microglia is a hallmark of several disorders of the central nervous system. In addn. to protecting the brain against inflammatory insults, microglia are neuroprotective and play a significant role in maintaining neuronal connectivity, but the prolongation of an inflammatory status may limit the beneficial functions of these immune cells. The finding that estrogen receptors are present in monocyte-derived cells and that estrogens prevent and control the inflammatory response raise the question of the role that this sex steroid plays in the manifestation and progression of pathologies that have a clear sex difference in prevalence, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The present review aims to provide a crit. review of the current literature on the actions of estrogen in microglia and on the involvement of estrogen receptors in the manifestation of selected neurol. disorders. This current understanding highlights a research area that should be expanded to identify appropriate replacement therapies to slow the progression of such diseases.
- 506Lewis, D. K.; Johnson, A. B.; Stohlgren, S.; Harms, A.; Sohrabji, F. Effects of Estrogen Receptor Agonists on Regulation of the Inflammatory Response in Astrocytes from Young Adult and Middle-Aged Female Rats. J. Neuroimmunol. 2008, 195 (1–2), 47– 59, DOI: 10.1016/j.jneuroim.2008.01.006[Crossref], [PubMed], [CAS], Google Scholar513https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkvVOrsbg%253D&md5=872374adfa200953c44d7fdada8f3951Effects of estrogen receptor agonists on regulation of the inflammatory response in astrocytes from young adult and middle-aged female ratsLewis, Danielle K.; Johnson, Adam B.; Stohlgren, Shannon; Harms, Ashley; Sohrabji, FaridaJournal of Neuroimmunology (2008), 195 (1-2), 47-59CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)Estrogen has been shown to attenuate the inflammatory response following injury or lipopolysaccharide treatment in several organ systems. Estrogen's actions are transduced through two estrogen receptor sub-types, estrogen receptor (ER) -alpha and estrogen receptor-beta, whose actions may be overlapping or independent of each other. The present study examd. the effects of ERα- and ERβ-specific ligands in regulating the inflammatory response in primary astrocyte cultures. Pre-treatment with 17β-estradiol (ERα/ERβ agonist), HPTE (ERα agonist/ERβ antagonist) and DPN (ERβ agonist) led to attenuation of IL-1β, TNFα, and MMP-9 in astrocyte media derived from young adult (3-4 mos.) and reproductive senescent female (9-11 mos., acyclic) astrocyte cultures, while pretreatment with PPT (ERα agonist) attenuated IL-1β (but not MMP-9) in both young and senescent-derived astrocyte cultures. Our previous work detd. that 17β-estradiol was unable to attenuate the LPS-induced increase in IL-1β in olfactory bulb primary microglial cultures derived from either young adult or reproductive senescent females. In young adult-derived microglial cultures, the LPS-induced increase in IL-1β was not attenuated by pre-treatment with 17β-estradiol, PPT or HPTE. Interestingly, the ERβ agonist, DPN significantly decreased IL-1β following LPS treatment in young adult-derived microglia. Thus while both microglia and astrocytes synthesize and release inflammatory mediators, the present data shows that compds. which bind ERβ are more effective in attenuating proinflammatory cytokines in both cell types and may therefore be a more effective agent for future therapeutic use.
- 507Vegeto, E.; Belcredito, S.; Etteri, S.; Ghisletti, S.; Brusadelli, A.; Meda, C.; Krust, A.; Dupont, S.; Ciana, P.; Chambon, P.; Maggi, A. Estrogen Receptor-α Mediates the Brain Antiinflammatory Activity of Estradiol. Proc. Natl. Acad. Sci. U. S. A. 2003, 100 (16), 9614– 9619, DOI: 10.1073/pnas.1531957100[Crossref], [PubMed], [CAS], Google Scholar514https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmtlyrsrk%253D&md5=6286a2e8b5ca38f34cdb10362e1c7644Estrogen receptor-α mediates the brain antiinflammatory activity of estradiolVegeto, Elisabetta; Belcredito, Silvia; Etteri, Sabrina; Ghisletti, Serena; Brusadelli, Alessia; Meda, Clara; Krust, Andree; Dupont, Sonia; Ciana, Paolo; Chambon, Pierre; Maggi, AdrianaProceedings of the National Academy of Sciences of the United States of America (2003), 100 (16), 9614-9619CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Beyond the key role in reproductive and cognitive functions, estrogens have been shown to protect against neurodegeneration assocd. with acute and chronic injuries of the adult brain. Current hypotheses reconcile this activity with a direct effect of 17β-estradiol (E2) on neurons. Brain macrophages are also involved in E2 action on the brain. Systemic administration of hormone prevents, in a time- and dose-dependent manner, the activation of microglia and the recruitment of peripheral monocytes induced by intraventricular injection of lipopolysaccharide. This effect occurs by limiting the expression of neuroinflammatory mediators, such as the matrix metalloproteinase 9 and lysosomal enzymes and complement C3 receptor, as well as by preventing morphol. changes occurring in microglia during the inflammatory response. By injecting lipopolysaccharide in estrogen receptor (ER)-null mouse brains, the authors demonstrate that hormone action is mediated by activation of ERα but not of ERβ. The specific role of ERα is further confirmed by comparing the effects of ERs on the matrix metalloproteinase 9 promoter activity in transient transfection assays. Finally, the authors report that genetic ablation of ERα is assocd. with a spontaneous reactive phenotype of microglia in specific brain regions of adult ERα-null mice. Altogether, these results reveal a previously undescribed function for E2 in brain and provide a mechanism for its beneficial activity on neuroinflammatory pathologies. They also underline the key role of ERα in brain macrophage reactivity and hint toward the usefulness of ERα-specific drugs in hormone replacement therapy of inflammatory diseases.
- 508Bebo, B. F.; Fyfe-Johnson, A.; Adlard, K.; Beam, A. G.; Vandenbark, A. A.; Offner, H. Low-Dose Estrogen Therapy Ameliorates Experimental Autoimmune Encephalomyelitis in Two Different Inbred Mouse Strains. J. Immunol. 2001, 166 (3), 2080– 2089, DOI: 10.4049/jimmunol.166.3.2080[Crossref], [PubMed], [CAS], Google Scholar515https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhtVSisbo%253D&md5=41d9a80d6e90b9194c05b113ee8cc91eLow-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strainsBebo, Bruce F., Jr.; Fyfe-Johnson, Amber; Adlard, Kirsten; Beam, Aaron G.; Vandenbark, Arthur A.; Offner, HalinaJournal of Immunology (2001), 166 (3), 2080-2089CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)It has been proposed that homeostatic levels of estrogen can enhance female susceptibility to autoimmunity, whereas the heightened levels of estrogen assocd. with pregnancy are protective. This hypothesis was tested using the mouse model of exptl. autoimmune encephalomyelitis (EAE). Diestrus (<100 pg/mL in serum) levels of 17β-estradiol were found to significantly reduce the clin. manifestations of active EAE in both male and female mice. Estriol was also effective but at doses below those previously established for pregnancy. The redn. in diseases severity was accompanied by a coincident redn. in the no. and size of inflammatory foci in the CNS of estrogen (17β-estradiol or estriol)-treated mice. Recipients of encephalitogenic T cells from low-dose estrogen-treated mice developed less severe paralysis than mice receiving T cells from placebo-treated mice. A modest shift in Th1/Th2 balance suggested that low dose estrogen therapy could bias the immune reaction toward a protective anti-inflammatory cytokine response. However, estrogen treatment at the onset of active EAE failed to reduce disease severity, a result that is consistent with the hypothesis that naive cells are more sensitive to sex hormones than differentiated effector cells. These data suggest that treatment with low doses of estrogen can reduce the capacity of developing myelin-reactive T cells to initiate disease and challenges the idea that increased susceptibility to autoimmunity in females is dependent on homeostatic levels of estrogen.
- 509Ito, A.; Bebo, B. F.; Matejuk, A.; Zamora, A.; Silverman, M.; Fyfe-Johnson, A.; Offner, H. Estrogen Treatment Down-Regulates TNF-α Production and Reduces the Severity of Experimental Autoimmune Encephalomyelitis in Cytokine Knockout Mice. J. Immunol. 2001, 167 (1), 542– 552, DOI: 10.4049/jimmunol.167.1.542[Crossref], [PubMed], [CAS], Google Scholar516https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXkslWjsL0%253D&md5=71c5a4fc4ad83f15089a61002bb01e78Estrogen treatment down-regulates TNF-α production and reduces the severity of experimental autoimmune encephalomyelitis in cytokine knockout miceIto, Atsushi; Bebo, Bruce F., Jr.; Matejuk, Agata; Zamora, Alex; Silverman, Marc; Fyfe-Johnson, Amber; Offner, HalinaJournal of Immunology (2001), 167 (1), 542-552CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)A shift toward Th2 cytokine prodn. has been demonstrated during pregnancy and high dose estrogen therapy and is thought to be the primary mechanism by which estrogen suppresses the development of exptl. autoimmune encephalomyelitis. However, low dose estrogen treatment is equally protective in the absence of a significant shift in cytokine prodn. In this study cytokine-deficient mice were treated with estrogen to det. whether a shift in Th2 cytokine prodn. was required for the protective effects of hormone therapy. Estrogen effectively suppressed the development of exptl. autoimmune encephalomyelitis in IL-4 and IL-10 knockout mice and in wild type littermate mice with a similar potency of protection. Significant disease suppression was also seen in IFN-γ-deficient mice. The decrease in disease severity was accompanied by a concomitant redn. in the no. of proinflammatory cytokine- and chemokine-producing cells in the CNS. Although there was no apparent increase in compensatory Th2 cytokine prodn. in cytokine-deficient mice, there was a profound decrease in the frequency of TNF-α-producing cells in the CNS and the periphery. Therefore, the authors propose that one mechanism by which estrogen protects females from the development of cell-mediated autoimmunity is through a hormone-dependent regulation of TNF-α prodn.
- 510Liu, H. Y.; Buenafe, A. C.; Matejuk, A.; Ito, A.; Zamora, A.; Dwyer, J.; Vandenbark, A. A.; Offner, H. Estrogen Inhibition of EAE Involves Effects on Dendritic Cell Function. J. Neurosci. Res. 2002, 70 (2), 238– 248, DOI: 10.1002/jnr.10409[Crossref], [PubMed], [CAS], Google Scholar517https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XnvFSlur4%253D&md5=34eae794c1b30db61d5287a3db89487cEstrogen inhibition of EAE involves effects on dendritic cell functionLiu, Hong Yan; Buenafe, Abigail C.; Matejuk, Agata; Ito, Atsushi; Zamora, Alex; Dwyer, Jami; Vandenbark, Arthur A.; Offner, HalinaJournal of Neuroscience Research (2002), 70 (2), 238-248CODEN: JNREDK; ISSN:0360-4012. (Wiley-Liss, Inc.)Estrogen has been found to have suppressive effects on the induction of exptl. autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. We have investigated the effects of 17β-estradiol (E2) treatment on dendritic cells (DCs) in two different mouse models of EAE. The frequency of CD11b+/CD11c+ DCs was significantly decreased in the brain of mice protected from EAE induction by E2 treatment. In addn., the frequency of CD11c+/CD8α+ DCs producing tumor necrosis factor (TNF)α and interferon (IFN)γ in the spleen of E2-treated mice was dramatically decreased compared to that in control mice with EAE, demonstrating an effect of E2 on DC function. In order to examine E2 effects on DCs in more detail, splenic DCs were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 to promote maturation. E2 pretreatment was found to suppress the ability of cultured DCs bearing a mature phenotype to present Ag to myelin basic protein (MBP)-specific T cells. Anal. of cytokine prodn. demonstrated that E2 decreased TNFα, IFNγ and IL-12 prodn. in mature DCs. In addn., MBP-specific T cells cocultured with E2-pretreated mature DCs in the presence of antigen demonstrated a shift towards prodn. of Th2 cytokines IL-4 and IL-10 and a concomitant decrease in the prodn. of Th1 cytokines TNFα and IFNγ. Thus, E2 treatment appears to have multiple effects on the DC population, which may contribute to a down-regulation or block in the activation of Th1 cells involved in the induction of EAE.
- 511Spence, R. D.; Hamby, M. E.; Umeda, E.; Itoh, N.; Du, S.; Wisdom, A. J.; Cao, Y.; Bondar, G.; Lam, J.; Ao, Y.; Sandoval, F.; Suriany, S.; Sofroniew, M. V.; Voskuhl, R. R. Neuroprotection Mediated through Estrogen Receptor-α in Astrocytes. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (21), 8867– 8872, DOI: 10.1073/pnas.1103833108[Crossref], [PubMed], [CAS], Google Scholar518https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntVegu7k%253D&md5=09da3b9932bf86a640ec1a0159148543Neuroprotection mediated through estrogen receptor-α in astrocytesSpence, Rory D.; Hamby, Mary E.; Umeda, Elizabeth; Itoh, Noriko; Du, Sienmi; Wisdom, Amy J.; Cao, Yuan; Bondar, Galyna; Lam, Jeannie; Ao, Yan; Sandoval, Francisco; Suriany, Silvie; Sofroniew, Michael V.; Voskuhl, Rhonda R.Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (21), 8867-8872, S8867/1-S8867/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Estrogen has well-documented neuroprotective effects in a variety of clin. and exptl. disorders of the CNS, including autoimmune inflammation, traumatic injury, stroke, and neurodegenerative diseases. The beneficial effects of estrogens in CNS disorders include mitigation of clin. symptoms, as well as attenuation of histopathol. signs of neurodegeneration and inflammation. The cellular mechanisms that underlie these CNS effects of estrogens are uncertain, because a no. of different cell types express estrogen receptors in the peripheral immune system and the CNS. Here, we investigated the potential roles of two endogenous CNS cell types in estrogen-mediated neuroprotection. We selectively deleted estrogen receptor-α (ERα) from either neurons or astrocytes using well-characterized Cre-loxP systems for conditional gene knockout in mice, and studied the effects of these conditional gene deletions on ERα ligand-mediated neuroprotective effects in a well-characterized model of adoptive exptl. autoimmune encephalomyelitis (EAE). We found that the pronounced and significant neuroprotective effects of systemic treatment with ERα ligand on clin. function, CNS inflammation, and axonal loss during EAE were completely prevented by conditional deletion of ERα from astrocytes, whereas conditional deletion of ERα from neurons had no significant effect. These findings show that signaling through ERα in astrocytes, but not through ERα in neurons, is essential for the beneficial effects of ERα ligand in EAE. Our findings reveal a unique cellular mechanism for estrogen-mediated CNS neuroprotective effects by signaling through astrocytes, and have implications for understanding the pathophysiol. of sex hormone effects in diverse CNS disorders.
- 512Kim, S.; Liva, S. M.; Dalal, M. A.; Verity, M. A.; Voskuhl, R. R. Estriol Ameliorates Autoimmune Demyelinating Disease: Implications for Multiple Sclerosis. Neurology 1999, 52 (6), 1230– 1238, DOI: 10.1212/WNL.52.6.1230[Crossref], [PubMed], [CAS], Google Scholar519https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXivVyqtL8%253D&md5=2b1a61a4d1f5a430ab48366141aba710Estriol ameliorates autoimmune demyelinating disease. Implications for multiple sclerosisKim, S.; Liva, S. M.; Dalal, M. A.; Verity, M. A.; Voskuhl, R. R.Neurology (1999), 52 (6), 1230-1238CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)To evaluate the use of estriol in the treatment of exptl. autoimmune encephalomyelitis (EAE) and other cell mediated autoimmune diseases. Exptl. autoimmune encephalomyelitis is a T helper 1 (Th1)-mediated autoimmune demyelinating disease that is a useful model for the study of immune responses in MS. Interestingly, both EAE and MS have been shown to be ameliorated during late pregnancy. Estriol, progesterone, and placebo pellets were implanted in mice during the effector phase of adoptive EAE. Disease scores were compared between treatment groups, and autoantigen-specific humoral and cellular responses were examd. Estriol treatment reduced the severity of EAE significantly compared with placebo treatment whereas progesterone treatment had no effect. Estriol doses that induced serum estriol levels that approximated estriol levels during late pregnancy were capable of ameliorating disease. Estriol-treated EAE mice had significantly higher levels of serum antibodies of the IgG1 isotype specific for the autoantigen myelin basic protein (MBP). Further, MBP-specific T-lymphocyte responses from estriol-treated EAE mice were characterized by significantly increased prodn. of the Th2 cytokine interleukin 10 (IL-10). T lymphocytes were shown to be the primary source of IL-10 within antigen-stimulated splenocyte populations. Estriol as a hormone involved in immune changes during pregnancy may provide a basis for the novel therapeutic use of estriol for MS and other putative Th1-mediated autoimmune diseases that improve during late pregnancy.
- 513Spence, R. D.; Wisdom, A. J.; Cao, Y.; Hill, H. M.; Mongerson, C. R. L.; Stapornkul, B.; Itoh, N.; Sofroniew, M. V.; Voskuhl, R. R. Estrogen Mediates Neuroprotection and Anti-Inflammatory Effects during EAE through ERα Signaling on Astrocytes but Not through ERβ Signaling on Astrocytes or Neurons. J. Neurosci. 2013, 33 (26), 10924– 10933, DOI: 10.1523/JNEUROSCI.0886-13.2013[Crossref], [PubMed], [CAS], Google Scholar520https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVKgu7nN&md5=95a24541ca9fd1877dbdb236e6d74b5fEstrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERα signaling on astrocytes but not through ERβ signaling on astrocytes or neuronsSpence, Rory D.; Wisdom, Amy J.; Cao, Yuan; Hill, Haley M.; Mongerson, Chandler R. L.; Stapornkul, Briana; Itoh, Noriko; Sofroniew, Michael V.; Voskuhl, Rhonda R.Journal of Neuroscience (2013), 33 (26), 10924-10933CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Estrogens can signal through either estrogen receptor α (ERα) or β (ERβ) to ameliorate exptl. autoimmune encephalomyelitis (EAE), the most widely used mouse model of multiple sclerosis (MS). Cellular targets of estrogen-mediated neuroprotection are still being elucidated. Previously, we demonstrated that ERα on astrocytes, but not neurons, was crit. for ERα ligand-mediated neuroprotection in EAE, including decreased T-cell and macrophage inflammation and decreased axonal loss. Here, we detd. whether ERβ on astrocytes or neurons could mediate neuroprotection in EAE, by selectively removing ERβ from either of these cell types using Cre-loxP gene deletion. Our results demonstrated that, even though ERβ ligand treatment was neuroprotective in EAE, this neuroprotection was not mediated through ERβ on either astrocytes or neurons and did not involve a redn. in levels of CNS inflammation. Given the differential neuroprotective and anti-inflammatory effects mediated via ERα vs. ERβ on astrocytes, we looked for mols. within astrocytes that were affected by signaling through ERα, but not ERβ. We found that ERα ligand treatment, but not ERβ ligand treatment, decreased expression of the chemokines CCL2 and CCL7 by astrocytes in EAE. Together, our data show that neuroprotection in EAE mediated via ERβ signaling does not require ERβ on either astrocytes or neurons, whereas neuroprotection in EAE mediated via ERα signaling requires ERα on astrocytes and reduces astrocyte expression of proinflammatory chemokines. These findings reveal important cellular differences in the neuroprotective mechanisms of estrogen signaling through ERα and ERβ in EAE.
- 514Sicotte, N. L.; Liva, S. M.; Klutch, R.; Pfeiffer, P.; Bouvier, S.; Odesa, S.; Wu, T. C. J.; Voskuhl, R. R. Treatment of Multiple Sclerosis with the Pregnancy Hormone Estriol. Ann. Neurol. 2002, 52 (4), 421– 428, DOI: 10.1002/ana.10301[Crossref], [PubMed], [CAS], Google Scholar521https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotlOjsbk%253D&md5=d862a1e452201bfbf1cc8acc831db03bTreatment of multiple sclerosis with the pregnancy hormone estriolSicotte, Nancy L.; Liva, Stephanie M.; Klutch, Rochelle; Pfeiffer, Paul; Bouvier, Seth; Odesa, Sylvia; Wu, T. C. Jackson; Voskuhl, Rhonda R.Annals of Neurology (2002), 52 (4), 421-428CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)Multiple sclerosis patients who become pregnant experience a significant decrease in relapses that may be mediated by a shift in immune responses from T helper 1 to T helper 2. Animal models of multiple sclerosis have shown that the pregnancy hormone, estriol, can ameliorate disease and can cause an immune shift. We treated nonpregnant female multiple sclerosis patients with the pregnancy hormone estriol in an attempt to recapitulate the beneficial effect of pregnancy. As compared with pretreatment baseline, relapsing remitting patients treated with oral estriol (8mg/day) demonstrated significant decreases in delayed type hypersensitivity responses to tetanus, interferon-γ levels in peripheral blood mononuclear cells, and gadolinium enhancing lesion nos. and vols. on monthly cerebral magnetic resonance images. When estriol treatment was stopped, enhancing lesions increased to pretreatment levels. When estriol treatment was reinstituted, enhancing lesions again were significantly decreased. Based on these results, a larger, placebo-controlled trial of estriol is warranted in women with relapsing remitting multiple sclerosis. This novel treatment strategy of using pregnancy doses of estriol in multiple sclerosis has relevance to other autoimmune diseases that also improve during pregnancy.
- 515Vukusic, S.; Ionescu, I.; El-Etr, M.; Schumacher, M.; Baulieu, E. E.; Cornu, C.; Confavreux, C. The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART′MUS) Trial: Rationale, Objectives and State of Advancement. J. Neurol. Sci. 2009, 286 (1–2), 114– 118, DOI: 10.1016/j.jns.2009.08.056[Crossref], [PubMed], [CAS], Google Scholar522https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1Cmur7P&md5=9c07fb1a6d469e5189a3ce0f437a8b98The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART'MUS) trial: Rationale, objectives and state of advancementVukusic, S.; Ionescu, I.; El-Etr, M.; Schumacher, M.; Baulieu, E. E.; Cornu, C.; Confavreux, C.Journal of the Neurological Sciences (2009), 286 (1-2), 114-118CODEN: JNSCAG; ISSN:0022-510X. (Elsevier B.V.)Multiple sclerosis (MS) affects 1 in 1000 people in western countries, mainly women in their childbearing years. It is an autoimmune disease of the central nervous system, which results in a chronic focal inflammatory response with subsequent demyelination and axonal loss. It usually begins with acute episodes of neurol. dysfunction, the relapses, followed by periods of partial or complete remission. This relapsing-remitting phase is usually followed by a steady, continuous and irreversible worsening of the neurol. dysfunction, which characterizes the progressive phase of the disease. Recent prospective studies reported a significant decline by two-third in the rate of relapses during the third trimester of pregnancy and a significant increase by two-third during the first three months post-partum by comparison to the relapse rate obsd. during the year prior to the pregnancy. These dramatic changes in the relapse rate occur at a time when impregnation of many substances, among which sexual steroids, is at its highest, before a dramatic decline to the pre-pregnancy levels, immediately following delivery. It may be hypothesized that sexual steroids could exert beneficial effects through a modulation of the immune state with a lowering of the pro-inflammatory lymphocyte responses of the Th1 type and an enhancement of anti-inflammatory responses of the Th2 type. They may also play a direct role in remyelination of central nervous system lesions, as they do in the peripheral nervous system, where progesterone increases the extent of myelin sheath formation after a cryolesion of the male mouse sciatic nerve. The POPART'MUS study is a European, multicenter, randomized, placebo-controlled and double-blind clin. trial, which aims to prevent MS relapses related to the post-partum condition, by administrating high doses of progestin, in combination with endometrial protective doses of estradiol. Treatment is given immediately after delivery and continuously during the first three months post-partum. At present, 126 patients have been enrolled and 107 patients have completed the protocol. Assuming the results of the trial to be pos., this new treatment could be considered in the relapsing-remitting phase of the disease in women afar from pregnancy and post-partum. The trial is registered under the ref. NTC00127075.
- 516Pozzilli, C.; De Giglio, L.; Barletta, V. T.; Marinelli, F.; De Angelis, F.; Gallo, V.; Pagano, V. A.; Marini, S.; Piattella, M. C.; Tomassini, V.; Pantano, P. Oral Contraceptives Combined with Interferon b in Multiple Sclerosis. Neurol. Neuroimmunol. NeuroInflammation 2015, 2 (4), e120, DOI: 10.1212/NXI.0000000000000120
- 517Voskuhl, R. R.; Wang, H. J.; Wu, T. C. J.; Sicotte, N. L.; Nakamura, K.; Kurth, F.; Itoh, N.; Bardens, J.; Bernard, J. T.; Corboy, J. R.; Cross, A. H.; Dhib-Jalbut, S.; Ford, C. C.; Frohman, E. M.; Giesser, B.; Jacobs, D.; Kasper, L. H.; Lynch, S.; Parry, G.; Racke, M. K.; Reder, A. T.; Rose, J.; Wingerchuk, D. M.; MacKenzie-Graham, A. J.; Arnold, D. L.; Tseng, C. H.; Elashoff, R. Estriol Combined with Glatiramer Acetate for Women with Relapsing-Remitting Multiple Sclerosis: A Randomised, Placebo-Controlled, Phase 2 Trial. Lancet Neurol. 2016, 15 (1), 35– 46, DOI: 10.1016/S1474-4422(15)00322-1[Crossref], [PubMed], [CAS], Google Scholar524https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFWlur3N&md5=c341048f0214951063df51f48472d3f0Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trialVoskuhl, Rhonda R.; Wang, HeJing; Wu, T. C. Jackson; Sicotte, Nancy L.; Nakamura, Kunio; Kurth, Florian; Itoh, Noriko; Bardens, Jenny; Bernard, Jacqueline T.; Corboy, John R.; Cross, Anne H.; Dhib-Jalbut, Suhayl; Ford, Corey C.; Frohman, Elliot M.; Giesser, Barbara; Jacobs, Dina; Kasper, Lloyd H.; Lynch, Sharon; Parry, Gareth; Racke, Michael K.; Reder, Anthony T.; Rose, John; Wingerchuk, Dean M.; MacKenzie-Graham, Allan J.; Arnold, Douglas L.; Tseng, Chi Hong; Elashoff, RobertLancet Neurology (2016), 15 (1), 35-46CODEN: LNAEAM; ISSN:1474-4422. (Elsevier Ltd.)Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclin. studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favorably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women. We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurol. centers in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 mo, with a significance level of p=0·10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Anal. was by intention to treat. The trial is registered with ClinicalTrials.gov, no. NCT00451204. We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0·25 relapses per yr (95% CI 0·17-0·37) in the estriol group vs. 0·37 relapses per yr (0·25-0·53) in the placebo group (adjusted rate ratio 0·63, 95% CI 0·37-1·05; p=0·077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0·0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0·0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clin. examn., mammogram, uterine ultrasound, or endometrial lining biopsy. Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 mo. These results warrant further investigation in a phase 3 trial. National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.
- 518Rossouw, J. E.; Anderson, G. L.; Prentice, R. L.; LaCroix, A. Z.; Kooperberg, C.; Stefanick, M. L.; Jackson, R. D.; Beresford, S. A. A.; Howard, B. V.; Johnson, K. C.; Kotchen, J. M.; Ockene, J. Risks and Benefits of Estrogen plus Progestin in Healthy Postmenopausal Women: Principal Results from the Women’s Health Initiative Randomized Controlled Trial. JAMA, J. Am. Med. Assoc. 2002, 288 (3), 321– 333, DOI: 10.1001/jama.288.3.321[Crossref], [PubMed], [CAS], Google Scholar525https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xltlegs7k%253D&md5=e1b284f6b24aca24dd44549ad91874d2Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the women's health initiative randomized controlled trialRossouw, Jacques E.; Anderson, Garnet L.; Prentice, Ross L.; LaCroix, Andrea Z.; Kooperberg, Charles; Stefanick, Marcia L.; Jackson, Rebecca D.; Beresford, Shirley A. A.; Howard, Barbara V.; Johnson, Karen C.; Morley-Kotchen, Jane; Ockene, JudithJAMA, the Journal of the American Medical Association (2002), 288 (3), 321-333CODEN: JAMAAP; ISSN:0098-7484. (American Medical Association)Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. Studies were carried out to assess the major health benefits and risks of the most commonly used combined hormone prepn. in the United States. The study design consisted of estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 yr) in which 16 608 postmenopausal women aged 50-79 yr with an intact uterus at baseline were recruited by 40 US clin. centers in 1993-1998. Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet or placebo. The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. On May 31, 2002, after a mean of 5.2 yr of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs. placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clin. outcomes through Apr. 30, 2002. Estd. hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Abs. excess risks per 10,000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while abs. risk redns. per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The abs. excess risk of events included in the global index was 19 per 10,000 person-years. Thus, overall health risks exceeded benefits from use of combined estrogen plus progestin for an av. 2-yr follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.
- 519Paterni, I.; Granchi, C.; Katzenellenbogen, J. A.; Minutolo, F. Estrogen Receptors Alpha (ERα) and Beta (ERβ): Subtype-Selective Ligands and Clinical Potential. Steroids 2014, 90, 13– 29, DOI: 10.1016/j.steroids.2014.06.012[Crossref], [PubMed], [CAS], Google Scholar526https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFenu7vI&md5=ac6863afe52e6a18ffd89d3ba6770023Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potentialPaterni, Ilaria; Granchi, Carlotta; Katzenellenbogen, John A.; Minutolo, FilippoSteroids (2014), 90 (), 13-29CODEN: STEDAM; ISSN:0039-128X. (Elsevier)A review. Estrogen receptors alpha (ERα) and beta (ERβ) are nuclear transcription factors that are involved in the regulation of many complex physiol. processes in humans. Modulation of these receptors by prospective therapeutic agents is currently being considered for prevention and treatment of a wide variety of pathol. conditions, such as, cancer, metabolic and cardiovascular diseases, neurodegeneration, inflammation, and osteoporosis. This review provides an overview and update of compds. that have been recently reported as modulators of ERs, with a particular focus on their potential clin. applications.
- 520Brzozowski, A. M.; Pike, A. C. W.; Dauter, Z.; Hubbard, R. E.; Bonn, T.; Engström, O.; Öhman, L.; Greene, G. L.; Gustafsson, J.-Å.; Carlquist, M. Molecular Basis of Agonism and Antagonism in the Oestrogen Receptor. Nature 1997, 389 (6652), 753– 758, DOI: 10.1038/39645[Crossref], [PubMed], [CAS], Google Scholar527https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmvVSnt74%253D&md5=2a63951b881b329ff142c9fbc82a13e3Molecular basis of agonism and antagonism in the estrogen receptorBrzozowski, Andrzej M.; Pike, Ashley C. W.; Dauter, Zbigniew; Hubbard, Roderick E.; Bonn, Tomas; Engstrom, Owe; Ohman, Lars; Greene, Geoffrey L.; Gustafsson, Jan-Ake; Carlquist, MatsNature (London) (1997), 389 (6652), 753-758CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)Estrogens are involved in the growth, development and homeostasis of a no. of tissues. The physiol. effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the estrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of mol. events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. Here we report the crystal structures of the LBD of ER in complex with the endogenous estrogen, 17β-estradiol, and the selective antagonist raloxifene, at resolns. of 3.1 and 2.6Å, resp. The structures provide a mol. basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes. In addn., each class of ligand induces a distinct conformation in the transactivation domain of the LBD, providing structural evidence of the mechanism of antagonism.
- 521Pike, A. C. W.; Brzozowski, A. M.; Hubbard, R. E.; Bonn, T.; Thorsell, A.-G.; Engström, O.; Ljunggren, J.; Gustafsson, J.-Å.; Carlquist, M. Structure of the Ligand-Binding Domain of Oestrogen Receptor Beta in the Presence of a Partial Agonist and a Full Antagonist. EMBO J. 1999, 18 (17), 4608– 4618, DOI: 10.1093/emboj/18.17.4608[Crossref], [PubMed], [CAS], Google Scholar528https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmt1yisLo%253D&md5=804a1a7c57ae5aed793f601241500febStructure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonistPike, Ashley C. W.; Brzozowski, Andrzej M.; Hubbard, Roderick E.; Bonn, Tomas; Thorsell, Ann-Gerd; Engstrom, Owe; Ljunggren, Jan; Gustafsson, Jan-Ake; Carlquist, MatsEMBO Journal (1999), 18 (17), 4608-4618CODEN: EMJODG; ISSN:0261-4189. (Oxford University Press)Estrogens exert their physiol. effects through two receptor subtypes. Here we report the three-dimensional structure of the estrogen receptor beta isoform (ERβ) ligand-binding domain (LBD) in the presence of the phyto-estrogen genistein and the antagonist raloxifene. The overall structure of ERβ-LBD is very similar to that previously reported for ERα. Each ligand interacts with a unique set of residues within the hormone-binding cavity and induces a distinct orientation in the AF-2 helix (H12). The bulky side chain of raloxifene protrudes from the cavity and phys. prevents the alignment of H12 over the bound ligand. In contrast, genistein is completely buried within the hydrophobic core of the protein and binds in a manner similar to that obsd. for ER's endogenous hormone, 17β-estradiol. However, in the ERβ-genistein complex, H12 does not adopt the distinctive "agonist" position but, instead, lies in a similar orientation to that induced by ER antagonists. Such a sub-optimal alignment of the transactivation helix is consistent with genistein's partial agonist character in ERβ and demonstrates how ER's transcriptional response to certain bound ligands is attenuated.
- 522Shiau, A. K.; Barstad, D.; Radek, J. T.; Meyers, M. J.; Nettles, K. W.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A.; Agard, D. A.; Greene, G. L. Structural Characterization of a Subtype-Selective Ligand Reveals a Novel Mode of Estrogen Receptor Antagonism. Nat. Struct. Biol. 2002, 9 (5), 359– 364, DOI: 10.1038/nsb787[Crossref], [PubMed], [CAS], Google Scholar529https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtFyrsrk%253D&md5=fb4b665e84466c50065a7b242104c364Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonismShiau, A. K.; Barstad, D.; Radek, J. T.; Meyers, M. J.; Nettles, K. W.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A.; Agard, D. A.; Greene, G. L.Nature Structural Biology (2002), 9 (5), 359-364CODEN: NSBIEW; ISSN:1072-8368. (Nature America Inc.)The R,R enantiomer of 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC) exerts opposite effects on the transcriptional activity of the two estrogen receptor (ER) subtypes, ERα and ERβ. THC acts as an ERα agonist and as an ERβ antagonist. We have detd. the crystal structures of the ERα ligand binding domain (LBD) bound to both THC and a fragment of the transcriptional coactivator GRIP1, and the ERβ LBD bound to THC. THC stabilizes a conformation of the ERα LBD that permits coactivator assocn. and a conformation of the ERβ LBD that prevents coactivator assocn. A comparison of the two structures, taken together with functional data, reveals that THC does not act on ERβ through the same mechanisms used by other known ER antagonists. Instead, THC antagonizes ERβ through a novel mechanism we term 'passive antagonism'.
- 523Levenson, A. S.; Craig Jordan, V. The Key to the Antiestrogenic Mechanism of Raloxifene Is Amino Acid 351 (Aspartate) in the Estrogen Receptor. Cancer Res. 1998, 58 (9), 1872– 1875[PubMed], [CAS], Google Scholar530https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXislentrs%253D&md5=3fd0451c44fa1112069453b6a8e8c496The key to the antiestrogenic mechanism of raloxifene is amino acid 351 (aspartate) in the estrogen receptorLevenson, Anait S.; Jordan, V. CraigCancer Research (1998), 58 (9), 1872-1875CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The crystn. of the ligand-binding domain (LBD) of the estrogen receptor (ER) with 17β-estradiol and raloxifene [A. M. Brzozowski et al., Nature (Lond.), 389: 753-758, 1997] now provides a mol. basis for the biol. activity of complexes as either agonists or antagonists. It is well established that the crit. structural feature of antiestrogens is a correctly positioned alkylaminoethoxy side chain. The X-ray crystallog. clearly shows that the alkylaminoethoxy side chain of raloxifene causes a specific and inappropriate mol. perturbation of the LBD and that the nitrogen in the side chain must hydrogen bond with aspartate 351 in the LBD of ER. We previously identified and characterized a naturally occurring mutation in the ER from a tamoxifen-stimulated transplantable human breast tumor line. The mutation is at AA351 of LBD, where the aspartate is changed to tyrosine (Asp351Tyr). In this report, we compared and contrasted the pharmacol. of raloxifene to block or induce E2-stimulated increase in TGF-α mRNA in stable transfectants of ER-neg. human breast cancer cells with the cDNAs from wild-type, mutant-amino acid (AA) 400 ER and mutant-AA 351 ER. Our results show that the mutation at AA 351 that replaces aspartate by tyrosine specifically changes the pharmacol. of raloxifene from an antiestrogen to an estrogen. By contrast, a mutation at AA 400 does not, and the antiestrogenic properties of raloxifene are retained. These data and the fact that the nitrogen in the side chain must specifically interact with aspartate 351 makes this the key to the antiestrogenic activity of raloxifene.
- 524Heldring, N.; Pike, A.; Andersson, S.; Matthews, J.; Cheng, G.; Hartman, J.; Tujague, M.; Ström, A.; Treuter, E.; Warner, M.; Gustafsson, J.-Å. Estrogen Receptors: How Do They Signal and What Are Their Targets. Physiol. Rev. 2007, 87 (3), 905– 931, DOI: 10.1152/physrev.00026.2006[Crossref], [PubMed], [CAS], Google Scholar531https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXptFGls7k%253D&md5=207d16fa37d6b14483b9fe1002ce2646Estrogen receptors: how do they signal and what are their targetsHeldring, Nina; Pike, Ashley; Andersson, Sandra; Matthews, Jason; Cheng, Guojun; Hartman, Johan; Tujague, Michel; Stroem, Anders; Treuter, Eckardt; Warner, Margaret; Gustafsson, Jan-AakePhysiological Reviews (2007), 87 (3), 905-931CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)A review. During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clin. as well as a preclin. perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ERα and ERβ) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clin. areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Mol. biol., biochem., and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a no. of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the mol. mechanisms of anti-estrogen signaling.
- 525Nilsson, S.; Koehler, K. F.; Gustafsson, J.-Å. Development of Subtype-Selective Oestrogen Receptor-Based Therapeutics. Nat. Rev. Drug Discovery 2011, 10 (10), 778– 792, DOI: 10.1038/nrd3551[Crossref], [PubMed], [CAS], Google Scholar532https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFOlsL7K&md5=dbd864f2c3be58434d21049568c1e348Development of subtype-selective oestrogen receptor-based therapeuticsNilsson, Stefan; Koehler, Konrad F.; Gustafsson, Jan-AakeNature Reviews Drug Discovery (2011), 10 (10), 778-792CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. The two estrogen receptor subtypes α and β are hormone-regulated modulators of intracellular signalling and gene expression. Regulation of estrogen receptor activity is crucial not only for development and homeostasis but also for the treatment of various diseases and symptoms. Classical selective estrogen receptor modulators are well established in the treatment of breast cancer and osteoporosis, but emerging data suggest that the development of subtype-selective ligands that specifically target either estrogen receptor-α or estrogen receptor-β could be a more optimal approach for the treatment of cancer, cardiovascular disease, multiple sclerosis and Alzheimer's disease.
- 526Jordan, V. C. Antiestrogens and Selective Estrogen Receptor Modulators as Multifunctional Medicines. 1. Receptor Interactions. J. Med. Chem. 2003, 46, 883– 908, DOI: 10.1021/jm020449y[ACS Full Text], [CAS], Google Scholar533https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhtl2ku78%253D&md5=b86cc4c3c4a4698a51eac9ab69ae9122Antiestrogens and Selective Estrogen Receptor Modulators as Multifunctional Medicines. 1. Receptor InteractionsJordan, V. CraigJournal of Medicinal Chemistry (2003), 46 (6), 883-908CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Antiestrogens and selective Estrogen receptor modulators as multifunctional medicines are discussed.
- 527Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Pyrazole Ligands: Structure - Affinity/Activity Relationships and Estrogen Receptor-α-Selective Agonists. J. Med. Chem. 2000, 43 (26), 4934– 4947, DOI: 10.1021/jm000170m[ACS Full Text], [CAS], Google Scholar534https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXot1yjsbk%253D&md5=3bce249ad2d0eaf91aa4ad17ebffdd05Pyrazole Ligands: Structure-Affinity/Activity Relationships and Estrogen Receptor-α-Selective AgonistsStauffer, Shaun R.; Coletta, Christopher J.; Tedesco, Rosanna; Nishiguchi, Gisele; Carlson, Kathryn; Sun, Jun; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.Journal of Medicinal Chemistry (2000), 43 (26), 4934-4947CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) and that one pyrazole is considerably more potent as an agonist on the ERα than on the ERβ subtype. To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ERα-selective agonist, we prepd. a no. of tetrasubstituted pyrazole analogs with defined variations at certain substituent positions. Anal. of their binding affinity pattern shows that a C(4)-Pr substituent is optimal and that a p-hydroxyl group on the N(1)-Ph group also enhances affinity and selectivity for ERα. The best compd. in this series, a propylpyrazole triol (I), binds to ERα with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ERα. It also activates gene transcription only through ERα. Thus, this compd. represents the first ERα-specific agonist. We investigated the mol. basis for the exceptional ERα binding affinity and potency selectivity of pyrazole I by a further study of structure-affinity relationships in this series and by mol. modeling. These investigations suggest that the pyrazole triols prefer to bind to ERα with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-Pr group with portions of the receptor where ERα has a smaller residue than ERβ. These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biol. activities in estrogen target cells that can be selectively activated through ERα.
- 528Meyers, M. J.; Sun, J.; Carlson, K. E.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Estrogen Receptor Subtype-Selective Ligands: Asymmetric Synthesis and Biological Evaluation of Cis- and Trans-5,11-Dialkyl-5,6,11,12- Tetrahydrochrysenes. J. Med. Chem. 1999, 42 (13), 2456– 2468, DOI: 10.1021/jm990101b[ACS Full Text], [CAS], Google Scholar535https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXjtlClt7Y%253D&md5=9e41afa29dec2419ab105ebb09615fb5Estrogen Receptor Subtype-Selective Ligands: Asymmetric Synthesis and Biological Evaluation of cis- and trans-5,11-Dialkyl- 5,6,11,12-tetrahydrochrysenesMeyers, Marvin J.; Sun, Jun; Carlson, Kathryn E.; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.Journal of Medicinal Chemistry (1999), 42 (13), 2456-2468CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)It was recently reported that racemic 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC) acts as an agonist on estrogen receptor alpha (ERα) and as a complete antagonist on estrogen receptor beta (ERβ). To further investigate this novel ER subtype-selective estrogenic activity, a series of cis- and trans-dialkyl THCs was synthesized. Cis-di-Me, cis-di-Et, and cis-di-Pr THCs were prepd. in a highly enantio- and diastereoselective manner by the acyloin condensation of enantiomerically pure α-alkyl-β-arylpropionic esters, followed by a Lewis acid-mediated double cyclization under conditions of minimal epimerization. ERα and ERβ binding affinity of both cis and trans isomers of di-Me, di-Et, and di-Pr THCs was detd. in competitive binding assays, and their transcriptional activity was detd. in reporter gene assays in mammalian cells. Nearly all THCs examd. were found to be affinity-selective for ERβ. All these THCs are agonists on ERα, and THCs with small substituents are agonists on both ERα and ERβ. As substituent size was increased, ERβ-selective antagonism developed first in the (R,R)-cis enantiomer series and finally in the trans diastereomer and (S,S)-cis enantiomer series. The most potent and selective ligand was identified as (R,R)-cis-diethyl THC 2b, which mimicked the ERβ-selective antagonist character of racemic cis-di-Et THC. This study illustrates that the antagonist character in THC ligands for ERβ depends in a progressive way on the size and geometric disposition of substituent groups and suggests that the induction of an antagonist conformation in ERβ can be achieved with these ligands with less steric perturbation than in ERα. Furthermore, antagonists that are selectively effective on ERβ can have structures that are very different from the typical antiestrogens tamoxifen and raloxifene, which are antagonists on both ERα and ERβ.
- 529Meyers, M. J.; Sun, J.; Carlson, K. E.; Marriner, G. A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Estrogen Receptor-β Potency-Selective Ligands: Structure-Activity Relationship Studies of Diarylpropionitriles and Their Acetylene and Polar Analogues. J. Med. Chem. 2001, 44 (24), 4230– 4251, DOI: 10.1021/jm010254a[ACS Full Text], [CAS], Google Scholar536https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnsFagsr8%253D&md5=8fbf46c36aaf2ffcc9a8c44b15827bfeEstrogen Receptor-β Potency-Selective Ligands: Structure-Activity Relationship Studies of Diarylpropionitriles and Their Acetylene and Polar AnaloguesMeyers, Marvin J.; Sun, Jun; Carlson, Kathryn E.; Marriner, Gwendolyn A.; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.Journal of Medicinal Chemistry (2001), 44 (24), 4230-4251CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Through an effort to develop novel ligands that have subtype selectivity for the estrogen receptors alpha (ERα) and beta (ERβ), we have found that 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) acts as an agonist on both ER subtypes, but has a 70-fold higher relative binding affinity and 170-fold higher relative potency in transcription assays with ERβ than with ERα. To investigate the ERβ affinity- and potency-selective character of this DPN further, we prepd. a series of DPN analogs in which both the ligand core and the arom. rings were modified by the repositioning of phenolic hydroxy groups and by the addn. of alkyl substituents and nitrile groups. We also prepd. other series of DPN analogs in which the nitrile functionality was replaced with acetylene groups or polar functions, to mimic the linear geometry or polarity of the nitrile, resp. To varying degrees, all of the analogs show preferential binding affinity for ERβ (i.e., they are ERβ affinity-selective), and many, but not all of them, are also more potent in activating transcription through ERβ than through ERα (i.e., they are ERβ potency-selective). meso-2,3-Bis(4-hydroxyphenyl)succinonitrile and dl-2,3-bis(4-hydroxyphenyl)succinonitrile are among the highest ERβ affinity-selective ligands, and they have an ERβ potency selectivity that is equiv. to that of DPN. The acetylene analogs have higher binding affinities but somewhat lower selectivities than their nitrile counterparts. The polar analogs have lower affinities, and only the fluorinated polar analogs have substantial affinity selectivities. This study suggests that, in this series of ligands, the nitrile functionality is crit. to ERβ selectivity because it provides the optimal combination of linear geometry and polarity. Furthermore, the addn. of a second nitrile group β to the nitrile in DPN or the addn. of a Me substituent at an ortho position on the β-arom. ring increases the affinity and selectivity of these compds. for ERβ. These ERβ-selective compds. may prove to be valuable tools in understanding the differences in structure and biol. function of ERα and ERβ.
- 530Minutolo, F.; Bertini, S.; Granchi, C.; Marchitiello, T.; Prota, G.; Rapposelli, S.; Tuccinardi, T.; Martinelli, A.; Gunther, J. R.; Carlson, K. E.; Katzenellenbogen, J. A.; Macchia, M. Structural Evolutions of Salicylaldoximes as Selective Agonists for Estrogen Receptor β. J. Med. Chem. 2009, 52 (3), 858– 867, DOI: 10.1021/jm801458t[ACS Full Text], [CAS], Google Scholar537https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktVygtw%253D%253D&md5=f3846088c752542e30c8590647a6c0daStructural Evolutions of Salicylaldoximes as Selective Agonists for Estrogen Receptor βMinutolo, Filippo; Bertini, Simone; Granchi, Carlotta; Marchitiello, Teresa; Prota, Giovanni; Rapposelli, Simona; Tuccinardi, Tiziano; Martinelli, Adriano; Gunther, Jillian R.; Carlson, Kathryn E.; Katzenellenbogen, John A.; Macchia, MarcoJournal of Medicinal Chemistry (2009), 52 (3), 858-867CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The bioisosteric replacement of the phenol ring, a signature functional group of most estrogen receptor (ER) ligands, with a hydrogen-bonded pseudocyclic ring, led to the development of a novel class of non-steroidal ER-ligands based on a salicylaldoxime template. A series of structural modifications were applied to selected mols. belonging to the monoaryl-salicylaldoxime chem. class in an attempt to improve further their ERβ-selective receptor affinity and agonist properties. Among several modifications, the best results were obtained by the simultaneous introduction of a meta-fluorine atom into the para-hydroxyphenyl substituent present in the 4-position of salicylaldoxime, together with the insertion of a chloro group in the 3-position of the central scaffold. The resulting compd. showed the best affinity (Ki = 7.1 nM) and selectivity for ERβ over ERα. Moreover, in transcription assays, it proved to be a selective and potent ERβ-full agonist with an EC50 of 4.8 nM.
- 531Malamas, M. S.; Manas, E. S.; McDevitt, R. E.; Gunawan, I.; Xu, Z. B.; Collini, M. D.; Miller, C. P.; Dinh, T.; Henderson, R. A.; Keith, J. C.; Harris, H. A. Design and Synthesis of Aryl Diphenolic Azoles as Potent and Selective Estrogen Receptor-β Ligands. J. Med. Chem. 2004, 47 (21), 5021– 5040, DOI: 10.1021/jm049719y[ACS Full Text], [CAS], Google Scholar538https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnt12gtrc%253D&md5=01c7d1d0fb71105c1adffeb5f0bc7d3bDesign and Synthesis of Aryl Diphenolic Azoles as Potent and Selective Estrogen Receptor-β LigandsMalamas, Michael S.; Manas, Eric S.; McDevitt, Robert E.; Gunawan, Iwan; Xu, Zhang B.; Collini, Michael D.; Miller, Chris P.; Dinh, Tam; Henderson, Ruth A.; Keith, James C., Jr.; Harris, Heather A.Journal of Medicinal Chemistry (2004), 47 (21), 5021-5040CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)New diphenolic azoles as highly selective estrogen receptor-β agonists are reported. The more potent and selective analogs of these series have comparable binding affinities for ERβ as the natural ligand 17β-estradiol but are >100-fold selective over ERα. The design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERβ cocrystd. with various ligands as well as mol. modeling studies. These strategies enabled the use of a single conservative residue substitution in the ligand-binding pocket, ERα Met421 → ERβ Ile373, to optimize ERβ selectivity. The 7-position-substituted benzoxazoles were the most selective ligands of both azole series, with ERB-041 (I) being >200-fold selective for ERβ. The majority of ERβ selective agonists tested that were at least ∼50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERβ-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
- 532Komm, B. S.; Mirkin, S. An Overview of Current and Emerging SERMs. J. Steroid Biochem. Mol. Biol. 2014, 143, 207– 222, DOI: 10.1016/j.jsbmb.2014.03.003[Crossref], [PubMed], [CAS], Google Scholar539https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVaksrjK&md5=18074eedb314d30864441d3f57cc4880An overview of current and emerging SERMsKomm, Barry S.; Mirkin, SebastianJournal of Steroid Biochemistry and Molecular Biology (2014), 143 (), 207-222CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)A review. Selective estrogen receptor modulators (SERMs) are compds. that exhibit tissue-specific estrogen receptor (ER) agonist or antagonist activity, and are used for various indications, including treatment of breast cancer, osteoporosis, and menopausal symptoms. Endometrial safety has been a key differentiator between SERMs in clin. practice. For example, tamoxifen exhibits ER agonist activity in the uterus, resulting in an increased risk of endometrial hyperplasia and malignancy, whereas raloxifene and bazedoxifene have neutral effects on the uterus. Based on their efficacy and long-term safety, SERMs are increasingly being prescribed for women who cannot tolerate other treatment options and for younger women at an increased risk of fracture who may remain on therapy for long periods of time. Continuing advances in the understanding of SERM mechanisms of action and structural interactions with the ER may lead to the development of new agents and combinations of agents to provide optimal treatments to meet the varying needs of postmenopausal women. One such example is the tissue selective estrogen complex, which partners a SERM with 1 or more estrogens, with the aim of blending the desired estrogen-receptor agonist activities of estrogens on vasomotor symptoms, vulvar-vaginal atrophy, and loss of bone mass with the tissue selectivity of a SERM.
- 533Patel, H. K.; Bihani, T. Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs) in Cancer Treatment. Pharmacol. Ther. 2018, 186, 1– 24, DOI: 10.1016/j.pharmthera.2017.12.012[Crossref], [PubMed], [CAS], Google Scholar540https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXovVShtw%253D%253D&md5=9e33ceed330cba071400fd70c0b71bf4Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatmentPatel, Hitisha K.; Bihani, TeeruPharmacology & Therapeutics (2018), 186 (), 1-24CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)Breast cancer is the most frequently diagnosed cancer in women, with estrogen receptor pos. (ER+) breast cancer making up approx. 75% of all breast cancers diagnosed. Given the dependence on active ER signaling in these tumors, the predominant treatment strategy has been to inhibit various aspects of this pathway including directly antagonizing ER with the use of selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). Interestingly, the dependence on ER for breast cancer growth is often retained even after progression through several lines of antiestrogen therapy, making ER a bonafide biomarker for this cancer subtype and driving the continued research and development of novel ER-targeted therapeutics to treat this patient population. This, combined with the continuous discovery of mechanisms underlying endocrine resistance, is resulting in a continually evolving treatment landscape for ER+ breast cancer. This review discusses various ER antagonists investigated for the treatment of breast cancer, outlining their pharmacol. and tissue-specific mechanisms of action as well as their specified use within the ER+ breast cancer setting. In addn., mechanisms of resistance to SERMs and SERDs, the use of ER antagonists in combination therapy strategies, and the ongoing development of novel drugs are also reviewed in the context of the changing clin. landscape of ER+ breast cancer. Lastly, the role of SERMs and SERDs in non-breast cancer indications is also discussed.
- 534Henke, B. R.; Drewry, D. H.; Jones, S. A.; Stewart, E. L.; Weaver, S. L.; Wiethe, R. W. 2-Amino-4,6-Diarylpyridines as Novel Ligands for the Estrogen Receptor. Bioorg. Med. Chem. Lett. 2001, 11 (14), 1939– 1942, DOI: 10.1016/S0960-894X(01)00321-3[Crossref], [PubMed], [CAS], Google Scholar541https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXltFylsb4%253D&md5=142e9f4a508e764440a048d657d6e0322-Amino-4,6-diarylpyridines as novel ligands for the estrogen receptorHenke, B. R.; Drewry, D. H.; Jones, S. A.; Stewart, E. L.; Weaver, S. L.; Wiethe, R. W.Bioorganic & Medicinal Chemistry Letters (2001), 11 (14), 1939-1942CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)A novel series of 2-amino-4,6-diarylpyridines were prepd. that function as ligands of estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). These compds. bind to both ERα and ERβ with a modest selectivity for the alpha subtype. The most potent of these analogs, compd. I, has a Ki=20 nM at ERα. These mols. represent a novel template for designing potentially useful ligands for the estrogen receptor.
- 535Renaud, J.; Bischoff, S. F.; Buhl, T.; Floersheim, P.; Fournier, B.; Geiser, M.; Halleux, C.; Kallen, J.; Keller, H.; Ramage, P. Selective Estrogen Receptor Modulators with Conformationally Restricted Side Chains. Synthesis and Structure-Activity Relationship of ERα-Selective Tetrahydroisoquinoline Ligands. J. Med. Chem. 2005, 48 (2), 364– 379, DOI: 10.1021/jm040858p[ACS Full Text], [CAS], Google Scholar542https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtFCiu7fN&md5=78fb4980fb466d857a1c767671dd0f31Selective Estrogen Receptor Modulators with Conformationally Restricted Side Chains. Synthesis and Structure-Activity Relationship of ERα-Selective Tetrahydroisoquinoline LigandsRenaud, Johanne; Bischoff, Serge Francois; Buhl, Thomas; Floersheim, Philipp; Fournier, Brigitte; Geiser, Martin; Halleux, Christine; Kallen, Joerg; Keller, Hansjoerg; Ramage, PaulJournal of Medicinal Chemistry (2005), 48 (2), 364-379CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors disclose herein the discovery of estrogen receptor α (ERα) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Mol. modeling studies used in conjunction with the x-ray crystal structure of the ERα ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compd. I was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline II. In addn. to exhibiting a binding affinity to ERα and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compd. I, ligand II showed a reduced agonist behavior in the MCF-7 assay in the absence of 17β-estradiol. These data point toward the fact that II may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic expt. carried out in rats, II displayed an interesting profile, with a bioavailability of 49%. The authors also disclose the x-ray crystal structure of II in complex with ERα-LBD, which reveals the preferred configurations of II at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogs bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted Ph D-ring increases the selectivity of a set of piperazinyl-contg. ligands in favor of ERα over ERβ.
- 536Hill, R. A.; Kouremenos, K.; Tull, D.; Maggi, A.; Schroeder, A.; Gibbons, A.; Kulkarni, J.; Sundram, S.; Du, X. Bazedoxifene – a Promising Brain Active SERM That Crosses the Blood Brain Barrier and Enhances Spatial Memory. Psychoneuroendocrinology 2020, 121, 104830, DOI: 10.1016/j.psyneuen.2020.104830[Crossref], [PubMed], [CAS], Google Scholar543https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1yjsLrJ&md5=d49dbaac0b1c60ca0b4b715df2182908Bazedoxifene - a promising brain active SERM that crosses the blood brain barrier and enhances spatial memoryHill, R. A.; Kouremenos, K.; Tull, D.; Maggi, A.; Schroeder, A.; Gibbons, A.; Kulkarni, J.; Sundram, S.; Du, X.Psychoneuroendocrinology (2020), 121 (), 104830CODEN: PSYCDE; ISSN:0306-4530. (Elsevier Ltd.)Over 20 years of accumulated evidence has shown that the major female sex hormone 17β-estradiol can enhance cognitive functioning. However, the utility of estradiol as a therapeutic cognitive enhancer is hindered by its unwanted peripheral effects (carcinogenic). Selective estrogen receptor modulators (SERMs) avoid the unwanted effects of estradiol by acting as estrogen receptor antagonists in some tissues such as breast and uterus, but as agonists in others such as bone, and are currently used for the treatment of osteoporosis. However, understanding of their actions in the brain are limited. The third generation SERM bazedoxifene has recently been FDA approved for clin. use with an improved biosafety profile. However, whether bazedoxifene can enter the brain and enhance cognition is unknown. Using mice, the current study aimed to explore if bazedoxifene can 1. cross the blood-brain barrier, 2. rescue ovariectomy-induced hippocampal-dependent spatial memory deficit, and 3. activity neural estrogen response element (ERE)-dependent gene transcription. Using liq. chromatog.-mass spectrometry (LC-MS), we firstly demonstrate that a peripheral injection of bazedoxifene can enter the brain. Secondly, we show that an acute i.p. injection of bazedoxifene can rescue ovariectomy-induced spatial memory deficits. And finally, using the ERE-luciferase reporter mouse, we show in vivo that bazedoxifene can activate the ERE in the brain. The evidence shown here suggest bazedoxifene could be a viable cognitive enhancer with promising clin. applicability.
- 537Wakeling, A. E.; Dukes, M.; Bowler, J. A Potent Specific Pure Antiestrogen with Clinical Potential. Cancer Res. 1991, 51 (15), 3867– 3873[PubMed], [CAS], Google Scholar544https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXlvFyrtr4%253D&md5=f73c3ea7810ce4780789bc69096f43eaA potent specific pure antiestrogen with clinical potentialWakeling, Alan E.; Dukes, Michael; Bowler, JeanCancer Research (1991), 51 (15), 3867-73CODEN: CNREA8; ISSN:0008-5472.Previous studies from this lab. have described a series of 7α-alkylamide analogs of estradiol with pure antiestrogenic activity, exemplified by ICI 164,384. A new compd., 7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17β-diol (ICI 182,780) has now been identified which has significantly increased antiestrogenic potency and retains pure estrogen antagonist activity. The antiuterotropic potency of ICI 182,780 in the immature rat was more than 10-fold greater than that of ICI 164,384 (50% EDs of 0.06 and 0.9 mg/kg, resp.). This order of magnitude increase of in vivo potency was also reflected, in part, by intrinsic activity at the estrogen receptor. The relative binding affinities of ICI 182,780 and ICI 164,384 were 0.89 and 0.19, resp., compared with that of estradiol (1.0). Similarly, the in vitro growth-inhibitory potency of ICI 182,780 exceeded that of ICI 164,384 in MCF-7 human breast cancer cells, where 50% inhibitory concns. of 0.29 and 1.3 nM, resp., were recorded. ICI 182,780 was a more effective inhibitor of MCF-7 growth than 4'-hydroxytamoxifen, producing an 80% redn. of cell no. under conditions where 4'-hydroxytamoxifen achieved a max. of 50% inhibition. This increased efficacy was reflected by a greater redn. of the proportion of cells engaged in DNA synthesis in ICI 182,780-treated cell cultures compared with tamoxifen-treated cells. Sustained antiestrogenic effects, following a single parental dose of ICI 182,780 in oil suspension, were apparent in both rats and pigtail monkeys. In vivo, antitumor activity of ICI 182,780 was demonstrated with xenografts of MCF-7 and Br10 human breast cancers in nude mice. A single injection of ICI 182,780 provided antitumor efficacy equiv. to that of daily tamoxifen treatment for at least 4 wk. The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer.
- 538Garner, F.; Shomali, M.; Paquin, D.; Lyttle, C. R.; Hattersley, G. RAD1901: A Novel, Orally Bioavailable Selective Estrogen Receptor Degrader That Demonstrates Antitumor Activity in Breast Cancer Xenograft Models. Anti-Cancer Drugs 2015, 26 (9), 948– 956, DOI: 10.1097/CAD.0000000000000271[Crossref], [PubMed], [CAS], Google Scholar545https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlGkt7vK&md5=acb860904a82a83b03b97b40420b64e1RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft modelsGarner, Fiona; Shomali, Maysoun; Paquin, Dotty; Lyttle, C. Richard; Hattersley, GaryAnti-Cancer Drugs (2015), 26 (9), 948-956CODEN: ANTDEV; ISSN:0959-4973. (Lippincott Williams & Wilkins)Agents that inhibit estrogen prodn., such as aromatase inhibitors or those that directly block estrogen receptor (ER) activity, such as selective estrogen receptor modulators and selective estrogen receptor degraders, are routinely used in the treatment of ER-pos. breast cancers. However, although initial treatment with these agents is often successful, many women eventually relapse with drug-resistant breast cancers. To overcome some of the challenges assocd. with current endocrine therapies and to combat the development of resistance, there is a need for more durable and more effective ER-targeted therapies. Here we describe and characterize a novel, orally bioavailable small-mol. selective estrogen receptor degrader, RAD1901, and evaluate its therapeutic potential for the treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-pos. breast cancer cell proliferation. Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models. In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-pos. breast cancer that has metastasized to the brain. Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues. RAD1901 is currently under clin. study in postmenopausal women with ER-pos. advanced breast cancer.
- 539Conlan, M. G.; de Vries, E. F. J.; Glaudemans, A.; Wang, Y.; Troy, S. Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women. Eur. J. Drug Metab. Pharmacokinet. 2020, 45 (5), 675– 689, DOI: 10.1007/s13318-020-00635-3[Crossref], [PubMed], [CAS], Google Scholar546https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlOisrzN&md5=96e466c99d3ca7bc506d5ff27e834f5bPharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal WomenConlan, Maureen G.; de Vries, Erik F. J.; Glaudemans, Awjm; Wang, Yamei; Troy, StevenEuropean Journal of Drug Metabolism and Pharmacokinetics (2020), 45 (5), 675-689CODEN: EJDPD2; ISSN:0378-7966. (Springer France)Abstr.: Background and Objectives: Advanced estrogen receptor-pos. (ER+) breast cancer is currently treated with endocrine therapy. Elacestrant is a novel, nonsteroidal, selective estrogen receptor degrader with complex dose-related ER agonist/antagonist activity that is being developed as a treatment option for ER+ breast cancer. Methods: Two first-in-human phase 1 studies of elacestrant in healthy postmenopausal women (Study 001/Study 004) were conducted to det. its pharmacokinetic and pharmacodynamic profile as well as its safety and max. tolerated dose. Results: In total, 140 postmenopausal subjects received at least one dose of study drug (114 received elacestrant and 26 received placebo). Single-ascending dose and multiple-ascending dose assessments showed that doses up to 1000 mg daily were safe and well tolerated, and the max. tolerated dose was not reached. Oral administration of elacestrant had an abs. bioavailability of 10% and a mean half-life ranging from 27 to 47 h, reaching steady state after 5-6 days. Mean occupancy of the ER in the uterus after seven daily doses was 83% for 200 mg and 92% for 500 mg daily. The median ratio of elacestrant concns. in the cerebral spinal fluid vs. plasma was 0.126% (500 mg dose) and 0.205% (200 mg dose). Most adverse events were related to the upper gastrointestinal tract.
Cited By
This article has not yet been cited by other publications.
Abstract
Figure 1
Figure 1. Nuclear receptors. (a) Overview over the nuclear receptor superfamily comprising 48 members in human.(30) (b) Basic mechanism of genomic nuclear receptor function. NRs of the NR1 family like LXRs and PPARs bind to their specific NRE within the promoter region of their target genes as obligate heterodimers with RXR. In the absence of ligand binding, these heterodimers associate with corepressor complexes, which results in repression of transcription. Conformational changes of the complex occur upon ligand binding, which involves displacement of the corepressor complex and subsequent coactivator recruitment, resulting in the transcription of target genes. (c) Exemplified indirect genomic action of nuclear receptors. For example, NFκB-regulated pro-inflammatory genes are differently controlled by NRs. Monomers such as PPARγ or LXR can undergo SUMOylation upon ligand binding and recruit corepressors to inhibit gene expression via NFκB (p50 and p65 subunits) interaction with its response elements.
Scheme 1
Scheme 1. Selected PPAR Ligands Used in Studies on Neurodegeneration or with Preferable Tool Compound CharacteristicsScheme 2
Scheme 2. RevERB ModulatorsScheme 3
Scheme 3. Selected LXR LigandsScheme 4
Scheme 4. Potent and Selective VDR Ligands (Agonists 37–40; Antagonist 41) from the Literature(214−217) as Potential Tools for Functional Studies in NeurodegenerationFigure 2
Figure 2. Role of RXR in NR heterodimers. Permissive heterodimers respond to RXR ligands and to ligands of the heterodimer partner. The presence of ligands for both partners causes synergistic activation. Nonpermissive heterodimers can only be activated by ligands of the heterodimer partner.(21)
Scheme 5
Scheme 5. Selected RXR LigandsScheme 6
Scheme 6. TLX Ligands Reported in the Literature(291,292,315)Figure 3
Figure 3. Comparison of the crystal structures of “classical” nuclear receptors (RXRα) and NR4A receptors (Nur77). (a) The apo structure of the RXRα LBD (pdb 3R29) in complex with the corepressor peptide SMRT (magenta) reveals the NR in its inactive state in which the C-terminal α-helix (H12, colored red) comprises the AF-2 in an unordered conformation. (b) The ligand-activated state of RXRα (pdb 3OAP) shows the NR cocrystallized with its endogenous ligand 9-cis RA (43) and the coactivator peptide TIF2 (neon green) with H12 in its active conformation. (c) The apo structure of the Nur77 LBD (pdb 3V3E) reveals the NR in an autoactivated state with H12 coordinated to the LBD core without a bound ligand. (d) Ligand-activated cocrystal structure (pdb 6KZ5) of the Nur77 LBD in complex with agonist Csn-B (68, purple) superimposed with ligand binding pockets and their respective ligands from other Nur77 cocrystal structures revealing other binding sites with high solvent exposure. Csn-B (68, purple) is bound at the dimeric interface, THPN (71, teal, pdb 4JGV) is protruding toward a sub-pocket between H5 and H7, and TMPA (69, blue and orange, pdb 3V3Q) is bound to two different sites. Site A (orange) is located at the interaction site of H12, which resembles the binding pockets identified for covalently bound Nurr1 ligands DHI (83) and PGA1 (80), while site B (blue) constitutes a cavity on the surface close to helices 1, 5, and 8. Alignment and superposition of the structures were performed in MOE 2020.09.
Scheme 7
Scheme 7. Nur77 Ligands Reported in the Literature(325,330,350,354,356,357)Figure 4
Figure 4. NR4A receptor mechanisms of action. (a) The constitutively active NR4A receptors (Nur77, Nurr1, and NOR-1) can directly bind to specific response elements as a homodimer, as a heterodimer with RXR (only Nur77 and Nurr1), or as a monomer. Sumoylation of the respective NR causes monomerization, and these monomers activate NBRE. NR4A homodimers bind to NurRE, while NR4A:RXR heterodimers bind to DR5 response elements. (b) Additionally, Nurr1 monomers directly interact with p65 on the NFκB RE upon sumoylation and recruit the CoREST corepressor complex, which results in suppression of NFκB-regulated pro-inflammatory genes. Abbreviations: CoREST, REST corepressor; DR5, direct repeat spaced by five nucleotides; NBRE, NGFI-B responsive element; NFκB, nuclear factor-κB; NOR-1, neuron derived orphan receptor 1; NurRE, Nur response element; Nurr1, nuclear receptor related-1 protein; RXR, retinoid X receptor.
Scheme 8
Scheme 8. Nurr1 Modulators Reported in the Literature(360,396−398,418,422)Scheme 9
Scheme 9. Nurr1-RXR Heterodimer-Specific RXR Agonists Reported in the Literature(402,403,435,436,438,439)Scheme 10
Scheme 10. NOR-1 Activating CompoundsScheme 11
Scheme 11. ER LigandsReferences
ARTICLE SECTIONSThis article references 539 other publications.
- 1Prince, M.; Bryce, R.; Albanese, E.; Wimo, A.; Ribeiro, W.; Ferri, C. P. The Global Prevalence of Dementia: A Systematic Review and Metaanalysis. Alzheimer's Dementia 2013, 9 (1), 63– 75.e2, DOI: 10.1016/j.jalz.2012.11.007[Crossref], [PubMed], [CAS], Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s3osVemsQ%253D%253D&md5=cbf1b2107d191f459ba6fe3e6194b3ecThe global prevalence of dementia: a systematic review and metaanalysisPrince Martin; Bryce Renata; Albanese Emiliano; Wimo Anders; Ribeiro Wagner; Ferri Cleusa PAlzheimer's & dementia : the journal of the Alzheimer's Association (2013), 9 (1), 63-75.e2 ISSN:.BACKGROUND: The evidence base on the prevalence of dementia is expanding rapidly, particularly in countries with low and middle incomes. A reappraisal of global prevalence and numbers is due, given the significant implications for social and public policy and planning. METHODS: In this study we provide a systematic review of the global literature on the prevalence of dementia (1980-2009) and metaanalysis to estimate the prevalence and numbers of those affected, aged ≥60 years in 21 Global Burden of Disease regions. RESULTS: Age-standardized prevalence for those aged ≥60 years varied in a narrow band, 5%-7% in most world regions, with a higher prevalence in Latin America (8.5%), and a distinctively lower prevalence in the four sub-Saharan African regions (2%-4%). It was estimated that 35.6 million people lived with dementia worldwide in 2010, with numbers expected to almost double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050. In 2010, 58% of all people with dementia lived in countries with low or middle incomes, with this proportion anticipated to rise to 63% in 2030 and 71% in 2050. CONCLUSION: The detailed estimates in this study constitute the best current basis for policymaking, planning, and allocation of health and welfare resources in dementia care. The age-specific prevalence of dementia varies little between world regions, and may converge further. Future projections of numbers of people with dementia may be modified substantially by preventive interventions (lowering incidence), improvements in treatment and care (prolonging survival), and disease-modifying interventions (preventing or slowing progression). All countries need to commission nationally representative surveys that are repeated regularly to monitor trends.
- 2Moutinho, M.; Codocedo, J. F.; Puntambekar, S. S.; Landreth, G. E. Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation. Annu. Rev. Pharmacol. Toxicol. 2019, 59, 237– 261[Crossref], [PubMed], [CAS], Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslSktrvJ&md5=f73dcd18cd535d4a8d041e843c11c92dNuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in TranslationMoutinho, Miguel; Codocedo, Juan F.; Puntambekar, Shweta S.; Landreth, Gary E.Annual Review of Pharmacology and Toxicology (2019), 59 (), 237-261CODEN: ARPTDI; ISSN:0362-1642. (Annual Reviews)A review. Neurodegenerative diseases are characterized by a progressive loss of neurons that leads to a broad range of disabilities, including severe cognitive decline and motor impairment, for which there are no effective therapies. Several lines of evidence support a putative therapeutic role of nuclear receptors (NRs) in these types of disorders. NRs are ligand-activated transcription factors that regulate the expression of a wide range of genes linked to metab. and inflammation. Although the activation of NRs in animal models of neurodegenerative disease exhibits promising results, the translation of this strategy to clin. practice has been unsuccessful. In this review we discuss the role of NRs in neurodegenerative diseases in light of preclin. and clin. studies, as well as new findings derived from the anal. of transcriptomic databases from humans and animal models. We discuss the failure in the translation of NR-based therapeutic approaches and consider alternative and novel research avenues in the development of effective therapies for neurodegenerative diseases.
- 3Abraha, I.; Rimland, J. M.; Trotta, F. M.; Dell’Aquila, G.; Cruz-Jentoft, A.; Petrovic, M.; Gudmundsson, A.; Soiza, R.; O’Mahony, D.; Guaita, A.; Cherubini, A. Systematic Review of Systematic Reviews of Non-Pharmacological Interventions to Treat Behavioural Disturbances in Older Patients with Dementia. The SENATOR-OnTop Series. BMJ. Open 2017, 7, e012759, DOI: 10.1136/bmjopen-2016-012759
- 4Schmidt, R.; Hofer, E.; Bouwman, F. H.; Buerger, K.; Cordonnier, C.; Fladby, T.; Galimberti, D.; Georges, J.; Heneka, M. T.; Hort, J.; Laczó, J.; Molinuevo, J. L.; O’Brien, J. T.; Religa, D.; Scheltens, P.; Schott, J. M.; Sorbi, S. EFNS-ENS/EAN Guideline on Concomitant Use of Cholinesterase Inhibitors and Memantine in Moderate to Severe Alzheimer’s Disease. Eur. J. Neurol. 2015, 22 (6), 889– 898, DOI: 10.1111/ene.12707[Crossref], [PubMed], [CAS], Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MnnvVejug%253D%253D&md5=29df2ef367c521b297d5621538032babEFNS-ENS/EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer's diseaseSchmidt R; Hofer E; Bouwman F H; Buerger K; Cordonnier C; Fladby T; Galimberti D; Georges J; Heneka M T; Hort J; Laczo J; Molinuevo J L; O'Brien J T; Religa D; Scheltens P; Schott J M; Sorbi SEuropean journal of neurology (2015), 22 (6), 889-98 ISSN:.BACKGROUND AND PURPOSE: Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer's disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL). METHODS: A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) -0.20; 95% confidence interval (CI) -0.31; -0.09], cognitive functioning (SMD -0.27, 95% CI -0.37; -0.17) and behaviour (SMD -0.19; 95% CI -0.31; -0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak. CONCLUSIONS: We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak.
- 5McShane, R.; Areosa Sastre, A.; Minakaran, N. Memantine for Dementia. Cochrane Database Syst. Rev. 2006, No. 2. DOI: 10.1002/14651858.CD003154.pub5
- 6Birks, J.; Grimley Evans, J. Ginkgo Biloba for Cognitive Impairment and Dementia. Cochrane Database Syst. Rev. 2009, No. 1. DOI: 10.1002/14651858.CD003120.pub3
- 7Masters, C. L.; Bateman, R.; Blennow, K.; Rowe, C. C.; Sperling, R. A.; Cummings, J. L. Alzheimer’s Disease. Nat. Rev. Dis. Prim. 2015, 1 (1), 15056, DOI: 10.1038/nrdp.2015.56
- 8Congdon, E. E.; Sigurdsson, E. M. Tau-Targeting Therapies for Alzheimer Disease. Nat. Rev. Neurol. 2018, 14 (7), 399– 415, DOI: 10.1038/s41582-018-0013-z[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFaks73M&md5=d26350964814206ce4860b7256c9d6a0Tau-targeting therapies for Alzheimer diseaseCongdon, Erin E.; Sigurdsson, Einar M.Nature Reviews Neurology (2018), 14 (7), 399-415CODEN: NRNACP; ISSN:1759-4758. (Nature Research)A review. Alzheimer disease (AD) is the most common form of dementia. Pathol., AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, with assocd. loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles, resp. In the decades since Aβ and tau were identified, development of therapies for AD has primarily focused on Aβ, but tau has received more attention in recent years, in part because of the failure of various Aβ-targeting treatments in clin. trials. In this article, we review the current status of tau-targeting therapies for AD. Initially, potential anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting therapies in clin. trials are immunotherapies, which have shown promise in numerous preclin. studies. Given that tau pathol. correlates better with cognitive impairments than do Aβ lesions, targeting of tau is expected to be more effective than Aβ clearance once the clin. symptoms are evident. With future improvements in diagnostics, these two hallmarks of the disease might be targeted prophylactically.
- 9Panza, F.; Lozupone, M.; Logroscino, G.; Imbimbo, B. P. A Critical Appraisal of Amyloid-β-Targeting Therapies for Alzheimer Disease. Nat. Rev. Neurol. 2019, 15 (2), 73– 88, DOI: 10.1038/s41582-018-0116-6[Crossref], [PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cnotFagtA%253D%253D&md5=fa63b5a3ca7e25169dfd6566f56b5152A critical appraisal of amyloid-β-targeting therapies for Alzheimer diseasePanza Francesco; Lozupone Madia; Logroscino Giancarlo; Panza Francesco; Logroscino Giancarlo; Panza Francesco; Imbimbo Bruno PNature reviews. Neurology (2019), 15 (2), 73-88 ISSN:.Brain accumulation of the amyloid-β (Aβ) peptide is believed to be the initial event in the Alzheimer disease (AD) process. Aβ accumulation begins 15-20 years before clinical symptoms occur, mainly owing to defective brain clearance of the peptide. Over the past 20 years, we have seen intensive efforts to decrease the levels of Aβ monomers, oligomers, aggregates and plaques using compounds that decrease production, antagonize aggregation or increase brain clearance of Aβ. Unfortunately, these approaches have failed to show clinical benefit in large clinical trials involving patients with mild to moderate AD. Clinical trials in patients at earlier stages of the disease are ongoing, but the initial results have not been clinically impressive. Efforts are now being directed against Aβ oligomers, the most neurotoxic molecular species, and monoclonal antibodies directed against these oligomers are producing encouraging results. However, Aβ oligomers are in equilibrium with both monomeric and aggregated species; thus, previous drugs that efficiently removed monomeric Aβ or Aβ plaques should have produced clinical benefits. In patients with sporadic AD, Aβ accumulation could be a reactive compensatory response to neuronal damage of unknown cause, and alternative strategies, including interference with modifiable risk factors, might be needed to defeat this devastating disease.
- 10Uliassi, E.; Gandini, A.; Perone, R. C.; Bolognesi, M. L. Neuroregeneration versus Neurodegeneration: Toward a Paradigm Shift in Alzheimer’s Disease Drug Discovery. Future Med. Chem. 2017, 9 (10), 995– 1013, DOI: 10.4155/fmc-2017-0038[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVCkt7nN&md5=bbbe7af9d8f6b0e7ad76e9c9a2561b5aNeuroregeneration versus neurodegeneration: toward a paradigm shift in Alzheimer's disease drug discoveryUliassi, Elisa; Gandini, Annachiara; Perone, Rosaria Carmela; Bolognesi, Maria LauraFuture Medicinal Chemistry (2017), 9 (10), 995-1013CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)Alzheimer's disease represents an enormous global burden in terms of human suffering and economic cost. To tackle the current lack of effective drugs and the continuous clin. trial failures might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting neural stem cells (NSCs) regeneration. In this context, small mols. have come to the forefront for their potential to manipulate NSCs, provide therapeutic tools and unveil NSCs biol. Classically, these mols. have been generated either by target-based or phenotypic approaches. To circumvent specific liabilities, nanomedicines emerge as a feasible alternative. However, this review is not intended to be comprehensive. Its purpose is to focus on recent examples that could accelerate development of neuroregenerative drugs against Alzheimer's disease.
- 11Wang, J.; Gu, B. J.; Masters, C. L.; Wang, Y.-J. A Systemic View of Alzheimer Disease — Insights from Amyloid-β Metabolism beyond the Brain. Nat. Rev. Neurol. 2017, 13 (10), 612– 623, DOI: 10.1038/nrneurol.2017.111[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFCrsL3F&md5=36954bc3ed9adb7b5c0111f177f02caaA systemic view of Alzheimer disease - insights from amyloid-β metabolism beyond the brainWang, Jun; Gu, Ben J.; Masters, Colin L.; Wang, Yan-JiangNature Reviews Neurology (2017), 13 (10), 612-623CODEN: NRNACP; ISSN:1759-4758. (Nature Research)A review. Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becoming more clearly defined. This Review focuses on amyloid-β (Aβ), a major hallmark of AD. We review emerging findings of assocns. between systemic abnormalities and Aβ metab., and describe how these assocns. might interact with or reflect on the central pathways of Aβ prodn. and clearance. On the basis of these findings, we propose that these abnormal systemic changes might not only develop secondary to brain dysfunction but might also affect AD progression, suggesting that the interactions between the brain and the periphery have a crucial role in the development and progression of AD. Such a systemic view of the mol. pathogenesis of AD could provide a novel perspective for understanding this disease and present new opportunities for its early diagnosis and treatment.
- 12Elkouzi, A.; Vedam-Mai, V.; Eisinger, R. S.; Okun, M. S. Emerging Therapies in Parkinson Disease — Repurposed Drugs and New Approaches. Nat. Rev. Neurol. 2019, 15 (4), 204– 223, DOI: 10.1038/s41582-019-0155-7[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cbjslGhsA%253D%253D&md5=5a3a423ad75f007ee27708cd0e80e6a2Emerging therapies in Parkinson disease - repurposed drugs and new approachesElkouzi Ahmad; Vedam-Mai Vinata; Eisinger Robert S; Okun Michael S; Vedam-Mai Vinata; Okun Michael SNature reviews. Neurology (2019), 15 (4), 204-223 ISSN:.Parkinson disease (PD) treatment options have conventionally focused on dopamine replacement and provision of symptomatic relief. Current treatments cause undesirable adverse effects, and a large unmet clinical need remains for treatments that offer disease modification and that address symptoms resistant to levodopa. Advances in high-throughput drug screening methods for small molecules, developments in disease modelling and improvements in analytical technologies have collectively contributed to the emergence of novel compounds, repurposed drugs and new technologies. In this Review, we focus on disease-modifying and symptomatic therapies under development for PD. We review cellular therapies and repurposed drugs, such as nilotinib, inosine, isradipine, iron chelators and anti-inflammatories, and discuss how their success in preclinical models has paved the way for clinical trials. We provide an update on immunotherapies and vaccines. In addition, we review non-pharmacological interventions targeting motor symptoms, including gene therapy, adaptive deep brain stimulation (DBS) and optogenetically inspired DBS. Given the many clinical phenotypes of PD, individualization of therapy and precision of treatment are likely to become important in the future.
- 13de Lau, L. M. L.; Breteler, M. M. B. Epidemiology of Parkinson’s Disease. Lancet Neurol. 2006, 5 (6), 525– 535, DOI: 10.1016/S1474-4422(06)70471-9[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD283osVehtg%253D%253D&md5=2c22b5eb8ff98db0a23d568123adea4bEpidemiology of Parkinson's diseasede Lau Lonneke M L; Breteler Monique M BThe Lancet. Neurology (2006), 5 (6), 525-35 ISSN:1474-4422.The causes of Parkinson's disease (PD), the second most common neurodegenerative disorder, are still largely unknown. Current thinking is that major gene mutations cause only a small proportion of all cases and that in most cases, non-genetic factors play a part, probably in interaction with susceptibility genes. Numerous epidemiological studies have been done to identify such non-genetic risk factors, but most were small and methodologically limited. Larger, well-designed prospective cohort studies have only recently reached a stage at which they have enough incident patients and person-years of follow-up to investigate possible risk factors and their interactions. In this article, we review what is known about the prevalence, incidence, risk factors, and prognosis of PD from epidemiological studies.
- 14Parkinson’s Disease in Adults. NICE Guidelines, 2017, NG71.
- 15Deuschl, G.; de Bie, R. M. A. New Therapeutic Developments for Parkinson Disease. Nat. Rev. Neurol. 2019, 15 (2), 68– 69, DOI: 10.1038/s41582-019-0133-0[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cjit1Gmug%253D%253D&md5=ccfa10002627723d357d778534ccb8deNew therapeutic developments for Parkinson diseaseDeuschl Gunther; de Bie Rob M ANature reviews. Neurology (2019), 15 (2), 68-69 ISSN:.There is no expanded citation for this reference.
- 16Doshi, A.; Chataway, J. Multiple Sclerosis, a Treatable Disease. Clin. Med. (Northfield. Il). 2016, 16 (6), s53– s59, DOI: 10.7861/clinmedicine.16-6-s53
- 17Tintore, M.; Vidal-Jordana, A.; Sastre-Garriga, J. Treatment of Multiple Sclerosis — Success from Bench to Bedside. Nat. Rev. Neurol. 2019, 15 (1), 53– 58, DOI: 10.1038/s41582-018-0082-z[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvV2qsb3O&md5=5067f9830346fe6e03cafd670e0ecfbbTreatment of multiple sclerosis - success from bench to bedsideTintore, Mar; Vidal-Jordana, Angela; Sastre-Garriga, JaumeNature Reviews Neurology (2019), 15 (1), 53-58CODEN: NRNACP; ISSN:1759-4758. (Nature Research)The modern era of multiple sclerosis (MS) treatment began 25 years ago, with the approval of IFNβ and glatiramer acetate for the treatment of relapsing-remitting MS. Ten years later, the first monoclonal antibody, natalizumab, was approved, followed by a third important landmark with the introduction of oral medications, initially fingolimod and then teriflunomide, di-Me fumarate and cladribine. Concomitantly, new monoclonal antibodies (alemtuzumab and ocrelizumab) have been developed and approved. The modern era of MS therapy reached primary progressive MS in 2018, with the approval of ocrelizumab. We have also learned the importance of starting treatment early and the importance of clin. and MRI monitoring to assess treatment response and safety. Treatment decisions should account for disease phenotype, prognostic factors, comorbidities, the desire for pregnancy and the patient's preferences in terms of acceptable risk. The development of treatment for MS during the past 25 years is a fantastic success of translational medicine.
- 18Stangel, M.; Kuhlmann, T.; Matthews, P. M.; Kilpatrick, T. J. Achievements and Obstacles of Remyelinating Therapies in Multiple Sclerosis. Nat. Rev. Neurol. 2017, 13 (12), 742– 754, DOI: 10.1038/nrneurol.2017.139[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M3itFaktg%253D%253D&md5=bfc226793aced3e8c04ce8b7306bbf20Achievements and obstacles of remyelinating therapies in multiple sclerosisStangel Martin; Kuhlmann Tanja; Matthews Paul M; Kilpatrick Trevor JNature reviews. Neurology (2017), 13 (12), 742-754 ISSN:.Remyelination in the CNS is the natural process of damage repair in demyelinating diseases such as multiple sclerosis (MS). However, remyelination becomes inadequate in many people with MS, which results in axonal degeneration and clinical disability. Enhancement of remyelination is a logical therapeutic goal; nevertheless, all currently licensed therapies for MS are immunomodulatory and do not support remyelination directly. Several molecular pathways have been identified as potential therapeutic targets to induce remyelination, and some of these have now been assessed in proof-of-concept clinical trials. However, trial design faces several obstacles: optimal clinical or paraclinical outcome measures to assess remyelination remain ill-defined, and identification of the ideal timing of therapy is also a crucial issue. In addition, realistic expectations are needed concerning the probable benefits of such therapies. Nevertheless, approaches that enhance remyelination are likely to be protective for axons and so could prevent long-term neurodegeneration. Future MS treatment paradigms, therefore, are likely to comprise a combinatorial approach that involves both immunomodulatory and regenerative treatments.
- 19Zhao, C.; Deng, W.; Gage, F. H. Mechanisms and Functional Implications of Adult Neurogenesis. Cell 2008, 132 (4), 645– 660, DOI: 10.1016/j.cell.2008.01.033[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXivVagtrY%253D&md5=8ab05939596eda4ed9fa77ed242e3c8fMechanisms and functional implications of adult neurogenesisZhao, Chunmei; Deng, Wei; Gage, Fred H.Cell (Cambridge, MA, United States) (2008), 132 (4), 645-660CODEN: CELLB5; ISSN:0092-8674. (Cell Press)A review. The generation of new neurons is sustained throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. We discuss the factors that regulate proliferation and fate detn. of adult neural stem cells and describe recent studies concerning the integration of newborn neurons into the existing neural circuitry. We further address the potential significance of adult neurogenesis in memory, depression, and neurodegenerative disorders such as Alzheimer's and Parkinson's disease.
- 20Germain, P.; Staels, B.; Dacquet, C.; Spedding, M.; Laudet, V. Overview of Nomenclature of Nuclear Receptors. Pharmacol. Rev. 2006, 58 (4), 685– 704, DOI: 10.1124/pr.58.4.2[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1ajtA%253D%253D&md5=264d69bdcd7b9f01f2d6ef3b73b78c60Overview of nomenclature of nuclear receptorsGermain, Pierre; Staels, Bart; Dacquet, Catherine; Spedding, Michael; Laudet, VincentPharmacological Reviews (2006), 58 (4), 685-704CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. Nuclear receptor pharmacol. has, to a certain extent, led the way, compared with other receptor systems, in the appreciation that ligands may exert very diverse pharmacol., based on their individual chem. structure and the allosteric changes induced in the receptor/accessory protein complex. This can lead to very selective pharmacol. effects, which may not necessarily be predicted from the experience with other agonists/partial agonists/antagonists. If this is the case, then drug discovery may be back to drug-specific pharmacol. (where each drug may have an original profile), rather than specific-drug pharmacol. (where agents specific for a receptor have a distinct profile). As functional selectivity is indeed a crucial mechanism to be considered when going through the drug discovery development process, then initial screens using reconstituted systems may not show the appropriate pharmacol., simply because the required stoichiometry of corepressors and coactivators may not be present to select the best compds.; therefore, multiple effector systems are necessary to screen for differential activation, and, even then, screening with in vivo pathophysiol. models may ultimately be required for the selection process-a massive but necessary task for pharmacologists. Thus, the characterization of nuclear receptors and their assocd. proteins and the ligands that interact with them will remain a challenge to pharmacologists.
- 21Aranda, A.; Pascual, A. Nuclear Hormone Receptors and Gene Expression. Physiol. Rev. 2001, 81 (3), 1269– 1304, DOI: 10.1152/physrev.2001.81.3.1269[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlt1Ohsrs%253D&md5=67ea9f6274b2a19bce09dd1c83a5f839Nuclear hormone receptors and gene expressionAranda, Ana; Pascual, AngelPhysiological Reviews (2001), 81 (3), 1269-1304CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)A review, with 324 refs. The nuclear hormone receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as different orphan receptors of unknown ligand. Ligands for some of these receptors have been recently identified, showing that products of lipid metab. such as fatty acids, prostaglandins, or cholesterol derivs. can regulate gene expression by binding to nuclear receptors. Nuclear receptors act as ligand-inducible transcription factors by directly interacting as monomers, homodimers, or heterodimers with the retinoid X receptor with DNA response elements of target genes, as well as by cross-talking to other signaling pathways. The effects of nuclear receptors on transcription are mediated through recruitment of coregulators. A subset of receptors binds corepressor factors and actively represses target gene expression in the absence of ligand. Corepressors are found within multicomponent complexes that contain histone deacetylase activity. Deacetylation leads to chromatin compaction and transcriptional repression. Upon ligand binding the receptors undergo a conformational change that allows the recruitment of multiple coactivator complexes. Some of these proteins are chromatin remodeling factors or possess histone acetylase activity whereas others may interact directly with the basic transcriptional machinery. Recruitment of coactivator complexes to the target promoter causes chromatin decompaction and transcriptional activation. The characterization of corepressor and coactivator complexes, in concert with the identification of the. Specific interaction motifs in the receptors, has demonstrated the existence of a general mol. mechanism by which different receptors elicit their transcriptional responses in target genes.
- 22De Bosscher, K.; Desmet, S. J.; Clarisse, D.; Estébanez-Perpiña, E.; Brunsveld, L. Nuclear Receptor Crosstalk — Defining the Mechanisms for Therapeutic Innovation. Nat. Rev. Endocrinol. 2020, 16 (7), 363– 377, DOI: 10.1038/s41574-020-0349-5[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnsVWltr8%253D&md5=22a5fe52c359ac1757d24fcde6d74a54Nuclear receptor crosstalk - defining the mechanisms for therapeutic innovationDe Bosscher, Karolien; Desmet, Sofie J.; Clarisse, Dorien; Estebanez-Perpina, Eva; Brunsveld, LucNature Reviews Endocrinology (2020), 16 (7), 363-377CODEN: NREABD; ISSN:1759-5029. (Nature Research)A review. Abstr.: Nuclear receptor crosstalk can be defined as the interplay between different nuclear receptors or between their overlapping signaling pathways. A subset of nuclear receptors (such as PPARs and RARs) engage in the formation of well-characterized 'typical' heterodimers with RXR. 'Atypical' heterodimers (such as GR with PPARs, or PPAR with ERR) might form a novel class of phys. complexes that might be more transient in nature. These heterodimers might harbor strong transcriptional flexibility, with no strict need for DNA binding of both partners. Direct crosstalk could stem from a pairwise phys. assocn. between atypical nuclear receptor heterodimers, either via pre-existing interaction pairs or via interactions that are newly induced with small mols.; such crosstalk might constitute an uncharted space to target nuclear receptor physiol. and/or pathophysiol. actions. In this Review, we discuss the emerging aspects of crosstalk in the nuclear receptor field and present various mechanistic crosstalk modes with examples that support applicability of the atypical heterodimer concept. Stabilization or disruption, in a context-dependent or cell type-dependent manner, of these more transient heterodimers is expected to fuel unprecedented translational approaches to yield novel therapeutic agents to treat major human diseases with higher precision.
- 23Evans, R. M.; Mangelsdorf, D. J. Nuclear Receptors, RXR, and the Big Bang. Cell 2014, 157, 255– 266, DOI: 10.1016/j.cell.2014.03.012[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmtVCqsLw%253D&md5=875fafc223c6585cf3494d3559357a4fNuclear Receptors, RXR, and the Big BangEvans, Ronald M.; Mangelsdorf, David J.Cell (Cambridge, MA, United States) (2014), 157 (1), 255-266CODEN: CELLB5; ISSN:0092-8674. (Cell Press)A review. Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional anal. revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the "Big Bang" of mol. endocrinol. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its assocd. ligands and transcriptional mechanism.
- 24Rastinejad, F.; Huang, P.; Chandra, V.; Khorasanizadeh, S. Understanding Nuclear Receptor Form and Function Using Structural Biology. J. Mol. Endocrinol. 2013, 51 (3), T1– T21, DOI: 10.1530/JME-13-0173[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXivFSnsbc%253D&md5=69abf902c2d99b23f37e33ceadd96016Understanding nuclear receptor form and function using structural biologyRastinejad, Fraydoon; Huang, Pengxiang; Chandra, Vikas; Khorasanizadeh, SepidehJournal of Molecular Endocrinology (2013), 51 (3), T1-T21CODEN: JMLEEI; ISSN:0952-5041. (BioScientifica Ltd.)A review. Nuclear receptors (NRs) are a major transcription factor family whose members selectively bind small-mol. lipophilic ligands and transduce those signals into specific changes in gene programs. For over two decades, structural biol. efforts were focused exclusively on the individual ligand-binding domains (LBDs) or DNA-binding domains of NRs. These analyses revealed the basis for both ligand and DNA binding and also revealed receptor conformations representing both the activated and repressed states. Addnl., crystallog. studies explained how NR LBD surfaces recognize discrete portions of transcriptional coregulators. The many structural snapshots of LBDs have also guided the development of synthetic ligands with therapeutic potential. Yet, the exclusive structural focus on isolated NR domains has made it difficult to conceptualize how all the NR polypeptide segments are coordinated phys. and functionally in the context of receptor quaternary architectures. Newly emerged crystal structures of the peroxisome proliferator-activated receptor-γ-retinoid X receptor α (PPARγ-RXRα) heterodimer and hepatocyte nuclear factor (HNF)-4α homodimer have recently revealed the higher order organizations of these receptor complexes on DNA, as well as the complexity and uniqueness of their domain-domain interfaces. These emerging structural advances promise to better explain how signals in one domain can be allosterically transmitted to distal receptor domains, also providing much better frameworks for guiding future drug discovery efforts.
- 25Negishi, M.; Kobayashi, K.; Sakuma, T.; Sueyoshi, T. Nuclear Receptor Phosphorylation in Xenobiotic Signal Transduction. J. Biol. Chem. 2020, 295 (45), 15210– 15225, DOI: 10.1074/jbc.REV120.007933[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38fkslOgsw%253D%253D&md5=c41bdaa5ededead6d6d5e2874d35ed52Nuclear receptor phosphorylation in xenobiotic signal transductionNegishi Masahiko; Kobayashi Kaoru; Sakuma Tsutomu; Sueyoshi TatsuyaThe Journal of biological chemistry (2020), 295 (45), 15210-15225 ISSN:.Nuclear pregnane X receptor (PXR, NR1I2) and constitutive active/androstane receptor (CAR, NR1I3) are nuclear receptors characterized in 1998 by their capability to respond to xenobiotics and activate cytochrome P450 (CYP) genes. An anti-epileptic drug, phenobarbital (PB), activates CAR and its target CYP2B genes, whereas PXR is activated by drugs such as rifampicin and statins for the CYP3A genes. Inevitably, both nuclear receptors have been investigated as ligand-activated nuclear receptors by identifying and characterizing xenobiotics and therapeutics that directly bind CAR and/or PXR to activate them. However, PB, which does not bind CAR directly, presented an alternative research avenue for an indirect ligand-mediated nuclear receptor activation mechanism: phosphorylation-mediated signal regulation. This review summarizes phosphorylation-based mechanisms utilized by xenobiotics to elicit cell signaling. First, the review presents how PB activates CAR (and other nuclear receptors) through a conserved phosphorylation motif located between two zinc fingers within its DNA-binding domain. PB-regulated phosphorylation at this motif enables nuclear receptors to form communication networks, integrating their functions. Next, the review discusses xenobiotic-induced PXR activation in the absence of the conserved DNA-binding domain phosphorylation motif. In this case, phosphorylation occurs at a motif located within the ligand-binding domain to transduce cell signaling that regulates hepatic energy metabolism. Finally, the review delves into the implications of xenobiotic-induced signaling through phosphorylation in disease development and progression.
- 26Rastinejad, F.; Ollendorff, V.; Polikarpov, I. Nuclear Receptor Full-Length Architectures: Confronting Myth and Illusion with High Resolution. Trends Biochem. Sci. 2015, 40 (1), 16– 24, DOI: 10.1016/j.tibs.2014.10.011[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFCnsbnM&md5=c290c02993f1dfda737ff644d309c7daNuclear receptor full-length architectures: confronting myth and illusion with high resolutionRastinejad, Fraydoon; Ollendorff, Vincent; Polikarpov, IgorTrends in Biochemical Sciences (2015), 40 (1), 16-24CODEN: TBSCDB; ISSN:0968-0004. (Elsevier Ltd.)A review. The crystal structures of 3 nuclear receptor (NR) complexes have emerged to reveal their multidomain architectures on DNA. These pictures provide unprecedented views of interfacial couplings between the DNA-binding domains (DBDs) and ligand-binding domains (LBDs). The detailed pictures contrast with previous interpretations of low-resoln. electron microscopy (EM) and small-angle X-ray scattering (SAXS) data, which had suggested a common architecture with non-interacting DBDs and LBDs. Revisiting both historical and recent interpretations of NR architecture, the authors invoke new principles underlying higher-order quaternary organization and the allosteric transmission of signals between domains. The authors also discuss how NR architectures are being probed in living cells to understand dimerization and DNA-binding events in real time.
- 27Weikum, E. R.; Liu, X.; Ortlund, E. A. The Nuclear Receptor Superfamily: A Structural Perspective. Protein Sci. 2018, 27, 1876– 1892, DOI: 10.1002/pro.3496[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvF2lt7zJ&md5=7ad0394bc664396a1945098246aa57b2The nuclear receptor superfamily: A structural perspectiveWeikum, Emily R.; Liu, Xu; Ortlund, Eric A.Protein Science (2018), 27 (11), 1876-1892CODEN: PRCIEI; ISSN:1469-896X. (Wiley-Blackwell)A review. Nuclear receptors (NRs) are a family of transcription factors that regulate numerous physiol. processes such as metab., reprodn., inflammation, as well as the circadian rhythm. NRs sense changes in lipid metabolite levels to drive differential gene expression, producing distinct physiol. effects. This is an allosteric process whereby binding a cognate ligand and specific DNA sequences drives the recruitment of diverse transcriptional co-regulators at chromatin and ultimately transactivation or transrepression of target genes. Dysregulation of NR signaling leads to various malignances, metabolic disorders, and inflammatory disease. Given their important role in physiol. and ability to respond to small lipophilic ligands, NRs have emerged as valuable therapeutic targets. Here, we summarize and discuss the recent progress on understanding the complex mechanism of action of NRs, primarily from a structural perspective. Finally, we suggest future studies to improve our understanding of NR signaling and better design drugs by integrating multiple structural and biophys. approaches.
- 28Bain, D. L.; Heneghan, A. F.; Connaghan-Jones, K. D.; Miura, M. T. Nuclear Receptor Structure: Implications for Function. Annu. Rev. Physiol. 2007, 69 (1), 201– 220, DOI: 10.1146/annurev.physiol.69.031905.160308[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXltVaks7o%253D&md5=e5a532a504e45489b84640efd7189f05Nuclear receptor structure: implications for functionBain, David L.; Heneghan, Aaron F.; Connaghan-Jones, Keith D.; Miura, Michael T.Annual Review of Physiology (2007), 69 (), 201-220CODEN: ARPHAD; ISSN:0066-4278. (Annual Reviews Inc.)A review. Small lipophilic mols. such as steroidal hormones, retinoids, and free fatty acids control many of the reproductive, developmental, and metabolic processes in eukaryotes. The mediators of these effects are nuclear receptor proteins, ligand-activated transcription factors capable of regulating the expression of complex gene networks. This review addresses the structure and structural properties of nuclear receptors, focusing on the well-studied ligand-binding and DNA-binding domains as well as the still-emerging understanding of the largely unstructured N-terminal regions. To emphasize the allosteric interdependence among these subunits, a more detailed inspection of the structural properties of the human progesterone receptor is presented. Finally, this work is placed in the context of developing a quant. and mechanistic understanding of nuclear receptor function.
- 29Benoit, G.; Cooney, A.; Giguere, V.; Ingraham, H.; Lazar, M.; Muscat, G.; Perlmann, T.; Renaud, J.-P.; Schwabe, J.; Sladek, F.; Tsai, M.-J.; Laudet, V. International Union of Pharmacology. LXVI. Orphan Nuclear Receptors. Pharmacol. Rev. 2006, 58 (4), 798– 836, DOI: 10.1124/pr.58.4.10[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1aitg%253D%253D&md5=dd46a5a87b58b13f720cd63d864b7c86International union of pharmacology. LXVI. Orphan nuclear receptorsBenoit, Gerard; Cooney, Austin; Giguere, Vincent; Ingraham, Holly; Lazar, Mitch; Muscat, George; Perlmann, Thomas; Renaud, Jean-Paul; Schwabe, John; Sladek, Frances; Tsai, Ming-Jer; Laudet, VincentPharmacological Reviews (2006), 58 (4), 798-836CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. Half of the members of the nuclear receptors superfamily are so-called "orphan" receptors because the identity of their ligand, if any, is unknown. Because of their important biol. roles, the study of orphan receptors has attracted much attention recently and has resulted in rapid advances that have helped in the discovery of novel signaling pathways. In this review we present the main features of orphan receptors, discuss the structure of their ligand-binding domains and their biol. functions. The paradoxical existence of a pharmacol. of orphan receptors, a rapidly growing and innovative field, is highlighted.
- 30Robinson-Rechavi, M.; Garcia, H. E.; Laudet, V. The Nuclear Receptor Superfamily. J. Cell Sci. 2003, 116 (4), 585– 586, DOI: 10.1242/jcs.00247[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252FjtFamuw%253D%253D&md5=ac244dd3bf3de2a5ff92fd43fe8f5959The nuclear receptor superfamilyRobinson-Rechavi Marc; Escriva Garcia Hector; Laudet VincentJournal of cell science (2003), 116 (Pt 4), 585-6 ISSN:0021-9533.There is no expanded citation for this reference.
- 31Michalik, L.; Auwerx, J.; Berger, J. P.; Chatterjee, V. K.; Glass, C. K.; Gonzalez, F. J.; Grimaldi, P. A.; Kadowaki, T.; Lazar, M. A.; O’Rahilly, S.; Palmer, C. N. A.; Plutzky, J.; Reddy, J. K.; Spiegelman, B. M.; Staels, B.; Wahli, W. International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors. Pharmacol. Rev. 2006, 58 (4), 726– 741, DOI: 10.1124/pr.58.4.5[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1ajuw%253D%253D&md5=938a3c0f6da60bde927e3b1822f7d12bInternational union of pharmacology. LXI. Peroxisome proliferator-activated receptorsMichalik, Liliane; Auwerx, Johan; Berger, Joel P.; Chatterjee, V. Krishna; Glass, Christopher K.; Gonzalez, Frank J.; Grimaldi, Paul A.; Kadowaki, Takashi; Lazar, Mitchell A.; O'Rahilly, Stephen; Palmer, Colin N. A.; Plutzky, Jorge; Reddy, Janardan K.; Spiegelman, Bruce M.; Staels, Bart; Wahli, WalterPharmacological Reviews (2006), 58 (4), 726-741CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. The three peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. They share a high degree of structural homol. with all members of the superfamily, particularly in the DNA-binding domain and ligand- and cofactor-binding domain. Many cellular and systemic roles have been attributed to these receptors, reaching far beyond the stimulation of peroxisome proliferation in rodents after which they were initially named. PPARs exhibit broad, isotype-specific tissue expression patterns. PPARα is expressed at high levels in organs with significant catabolism of fatty acids. PPARβ/δ has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPARγ is expressed as two isoforms, of which PPARγ2 is found at high levels in the adipose tissues, whereas PPARγ1 has a broader expression pattern. Transcriptional regulation by PPARs requires heterodimerization with the retinoid X receptor (RXR). When activated by a ligand, the dimer modulates transcription via binding to a specific DNA sequence element called a peroxisome proliferator response element (PPRE) in the promoter region of target genes. A wide variety of natural or synthetic compds. was identified as PPAR ligands. Among the synthetic ligands, the lipid-lowering drugs, fibrates, and the insulin sensitizers, thiazolidinediones, are PPARα and PPARγ agonists, resp., which underscores the important role of PPARs as therapeutic targets. Transcriptional control by PPAR/RXR heterodimers also requires interaction with coregulator complexes. Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities.
- 32Warden, A.; Truitt, J.; Merriman, M.; Ponomareva, O.; Jameson, K.; Ferguson, L. B.; Mayfield, R. D.; Harris, R. A. Localization of PPAR Isotypes in the Adult Mouse and Human Brain. Sci. Rep. 2016, 6, 27681, DOI: 10.1038/srep27618
- 33Gellrich, L.; Heitel, P.; Heering, J.; Kilu, W.; Pollinger, J.; Goebel, T.; Kahnt, A.; Arifi, S.; Pogoda, W.; Paulke, A.; Steinhilber, D.; Proschak, E.; Wurglics, M.; Schubert-Zsilavecz, M.; Chaikuad, A.; Knapp, S.; Bischoff, I.; Fürst, R.; Merk, D. L-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ. J. Med. Chem. 2020, 63 (13), 6727– 6740, DOI: 10.1021/acs.jmedchem.9b02150[ACS Full Text], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXotl2qt7k%253D&md5=ef11092bf1432477ab92bda15bf37c46L-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγGellrich, Leonie; Heitel, Pascal; Heering, Jan; Kilu, Whitney; Pollinger, Julius; Goebel, Tamara; Kahnt, Astrid; Arifi, Silvia; Pogoda, Werner; Paulke, Alexander; Steinhilber, Dieter; Proschak, Ewgenij; Wurglics, Mario; Schubert-Zsilavecz, Manfred; Chaikuad, Apirat; Knapp, Stefan; Bischoff, Iris; Fuerst, Robert; Merk, DanielJournal of Medicinal Chemistry (2020), 63 (13), 6727-6740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Thyroid hormones (THs) operate numerous physiol. processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and non-classical THs as another mol. activity of THs. The T4 metabolite TETRAC was the most active TH on PPARγ with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular and in vivo settings. Simultaneous activation of the heterodimer partners PPARγ and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARγ and RXR, TETRAC differs markedly in its mol. structure and the PPARγ-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacol.
- 34Proschak, E.; Heitel, P.; Kalinowsky, L.; Merk, D. Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery. J. Med. Chem. 2017, 60 (13), 5235– 5266, DOI: 10.1021/acs.jmedchem.6b01287[ACS Full Text], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjs1elsrw%253D&md5=78a3a6be0a9d9bfd672c5e851abffc3eOpportunities and Challenges for Fatty Acid Mimetics in Drug DiscoveryProschak, Ewgenij; Heitel, Pascal; Kalinowsky, Lena; Merk, DanielJournal of Medicinal Chemistry (2017), 60 (13), 5235-5266CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Fatty acids beyond their role as an endogenous energy source and storage are increasingly considered as signaling mols. regulating various physiol. effects in metab. and inflammation. Accordingly, the mol. targets involved in formation and physiol. activities of fatty acids hold significant therapeutic potential. A no. of these fatty acid targets are addressed by some of the oldest and most widely used drugs such as cyclooxygenase inhibiting NSAIDs, whereas others remain unexploited. Compds. orthosterically binding to proteins that endogenously bind fatty acids are considered as fatty acid mimetics. On the basis of their structural resemblance, fatty acid mimetics constitute a family of bioactive compds. showing specific binding thermodn. and following similar pharmacokinetic mechanisms. This perspective systematically evaluates targets for fatty acid mimetics, investigates their common structural characteristics, and highlights demands in their discovery and design. In summary, fatty acid mimetics share particularly favorable characteristics justifying the conclusion that their therapeutic potential vastly outweighs the challenges in their design.
- 35Wahli, W.; Michalik, L. PPARs at the Crossroads of Lipid Signaling and Inflammation. Trends Endocrinol. Metab. 2012, 23, 351– 363, DOI: 10.1016/j.tem.2012.05.001[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XosFChur4%253D&md5=c75c774b268207244eb1ba0e476633efPPARs at the crossroads of lipid signaling and inflammationWahli, Walter; Michalik, LilianeTrends in Endocrinology and Metabolism (2012), 23 (7), 351-363CODEN: TENME4; ISSN:1043-2760. (Elsevier Ltd.)A review. Nuclear receptors (NRs) are ligand-dependent transcription factors whose activation affects genes controlling vital processes. Among them, the peroxisome proliferator-activated receptors (PPARs) have emerged as links between lipids, metabolic diseases, and innate immunity. PPARs are activated by fatty acids and their derivs., many of which also signal through membrane receptors, thereby creating a lipid signaling network between the cell surface and the nucleus. Tissues that play a role in whole-body metabolic homeostasis, such as adipose tissue, liver, skeletal muscle, intestines, and blood vessel walls, are prone to inflammation when metab. is disturbed, a complication that promotes type 2 diabetes and cardiovascular disease. This review discusses the protective roles of PPARs in inflammatory conditions and the therapeutic anti-inflammatory potential of PPAR ligands.
- 36Lamers, C.; Schubert-Zsilavecz, M.; Merk, D. Therapeutic Modulators of Peroxisome Proliferator-Activated Receptors (PPAR): A Patent Review (2008–Present). Expert Opin. Ther. Pat. 2012, 22 (7), 803– 841, DOI: 10.1517/13543776.2012.699042[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XptVGrtbw%253D&md5=302d4f63a185c451514dd032becc3c3bTherapeutic modulators of peroxisome proliferator-activated receptors (PPAR): a patent review (2008-present)Lamers, Christina; Schubert-Zsilavecz, Manfred; Merk, DanielExpert Opinion on Therapeutic Patents (2012), 22 (7), 803-841CODEN: EOTPEG; ISSN:1354-3776. (Informa Healthcare)A review. Introduction: Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. The three known subtypes PPARα, PPARγ and PPARδ have different tissue distribution and play a key role as regulators of glucose and lipid homeostasis as well as in cell proliferation, differentiation and inflammatory responses. They have gained a lot of interest as pharmaceutical targets over the last years and with the antidiabetic thiazolidindiones (TZDs) and the hypolipidemic fibrates, two classes of drugs had entered the market. Early observations of severe adverse events changed the situation in the recent past. Areas covered: Herein the authors summarize recent (2008-present) patent applications concerning PPAR ligands claimed for the use in metabolic disorders as well as patents indicating new applications for modulators of the PPAR subtypes.Expert opinion: Looking at the recent patent activity regarding novel compds., there have not been real innovations. As major applications for therapeutic PPAR ligands cancer therapy, skin-related disorders and systemic anti-inflammatory therapies might arise in the mid-term future. The known PPAR targeting drugs might see a repurposing for novel indications.
- 37Lu, C.-H.; Yang, C.-Y.; Li, C.-Y.; Hsieh, C.; Ou, H.-T. Lower Risk of Dementia with Pioglitazone, Compared with Other Second-Line Treatments, in Metformin-Based Dual Therapy: A Population-Based Longitudinal Study. Diabetologia 2018, 61 (3), 562– 573, DOI: 10.1007/s00125-017-4499-5[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVSmsLjP&md5=9b392b0512f3e11c9f7a627fe6b751bbLower risk of dementia with pioglitazone, compared with other second-line treatments, in metformin-based dual therapy: a population-based longitudinal studyLu, Chieh-Hsiang; Yang, Chen-Yi; Li, Chung-Yi; Hsieh, Cheng-Yang; Ou, Huang-TzDiabetologia (2018), 61 (3), 562-573CODEN: DBTGAJ; ISSN:0012-186X. (Springer)Aims/hypothesis: The effect of pioglitazone was compared with that of other second-line glucose-lowering drugs on the risk of dementia among individuals with type 2 diabetes receiving metformin-based dual therapy. Methods: A total of 204,323 individuals with type 2 diabetes aged ≥18 years who were stable metformin users and dementia-free before the initiation of second-line glucose-lowering medication were identified in the period 2000-2011 from Taiwan's National Health Insurance Research Database and followed to the end of 2013. Primary analyses included 51,415 individuals aged ≥65 years without dementia events in the first year of second-line glucose-lowering treatment. Study subjects were classified into mutually exclusive groups according to various second-line glucose-lowering drugs to metformin. Cox proportional hazards models were applied to assess the time-to-event between propensity score-matched glucose-lowering treatment groups. Results: Individuals aged ≥65 years on metformin + pioglitazone had a significantly lower risk of dementia compared with those on metformin + sulfonylurea (HR 0.56; 95% CI 0.34, 0.93), and a lower, but insignificant, risk of dementia compared with those on other metformin-based dual regimens (i.e. metformin + acarbose, metformin + meglitinide, metformin + insulin or metformin + dipeptidyl peptidase 4 inhibitors). Among individuals aged ≥18 years, there was also a decreased risk of dementia in those taking pioglitazone compared with those taking other second-line glucose-lowering drugs. A lower incidence of dementia was found in users of metformin + pioglitazone compared with users of metformin + rosiglitazone. Conclusions/interpretation: Pioglitazone as a second-line treatment after metformin might provide a protective effect on dementia risk among individuals with type 2 diabetes.
- 38Heneka, M. T.; Fink, A.; Doblhammer, G. Effect of Pioglitazone Medication on the Incidence of Dementia. Ann. Neurol. 2015, 78 (2), 284– 294, DOI: 10.1002/ana.24439[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KmsLbJ&md5=9eecf871dfb506e716f9518f86542655Effect of pioglitazone medication on the incidence of dementiaHeneka, Michael T.; Fink, Anne; Doblhammer, GabrieleAnnals of Neurology (2015), 78 (2), 284-294CODEN: ANNED3; ISSN:0364-5134. (John Wiley & Sons, Inc.)Objective : Peroxisome proliferator activated receptor γ-activating drugs show various salutary effects in preclin. models of neurodegenerative disease. The decade-long clin. usage of these drugs as antidiabetics now allows for evaluation of patient-oriented data sources. Methods : Using observational data from 2004-2010, we analyzed the assocn. of pioglitazone and incidence of dementia in a prospective cohort study of 145,928 subjects aged ≥60 years who, at baseline, were free of dementia and insulin-dependent diabetes mellitus. We distinguished between nondiabetics, diabetics without pioglitazone, diabetics with prescriptions of <8 calendar quarters of pioglitazone, and diabetics with ≥8 quarters. Cox proportional hazard models explored the relative risk (RR) of dementia incidence dependent on pioglitazone use adjusted for sex, age, use of rosiglitazone or metformin, and cardiovascular comorbidities. Results : Long-term use of pioglitazone was assocd. with a lower dementia incidence. Relative to nondiabetics, the cumulative long-term use of pioglitazone reduced the dementia risk by 47% (RR = 0.53, p = 0.029). If diabetes patients used pioglitazone <8 quarters, the dementia risk was comparable to those of nondiabetics (RR = 1.16, p = 0.317), and diabetes patients without a pioglitazone treatment had a 23% increase in dementia risk (RR = 1.23, p < 0.001). We did not find evidence for age effects, nor for selection into pioglitazone treatment due to obesity. Interpretation : These findings indicate that pioglitazone treatment is assocd. with a reduced dementia risk in initially non-insulin-dependent diabetes mellitus patients. Prospective clin. trials are needed to evaluate a possible neuroprotective effect in these patients in an ageing population. Ann Neurol 2015;78:284-294.
- 39Chou, P.-S.; Ho, B.-L.; Yang, Y.-H. Effects of Pioglitazone on the Incidence of Dementia in Patients with Diabetes. J. Diabetes Complications 2017, 31 (6), 1053– 1057, DOI: 10.1016/j.jdiacomp.2017.01.006[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czitlSitA%253D%253D&md5=d35451551f14800a3f1ba2a1d796ad33Effects of pioglitazone on the incidence of dementia in patients with diabetesChou Ping-Song; Ho Bo-Lin; Yang Yuan-HanJournal of diabetes and its complications (2017), 31 (6), 1053-1057 ISSN:.AIMS: Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists exert neuroprotective effects in the brain. Therefore, in this population-based cohort study, we investigated the effects of pioglitazone, a PPAR-γ agonist, on the risk of dementia. METHODS: By using claims data from Taiwan's National Health Insurance Research Database, we included 6401 patients with diabetes who were treated with pioglitazone and 12,802 age- and sex-matched patients with diabetes who were never treated with pioglitazone from 2004 to 2009 and who were free of dementia at baseline. RESULTS: In total, 113 (1.8%) and 323 (2.5%) patients in the pioglitazone-treated and comparison cohorts, respectively, developed dementia during the 5-year follow-up. The risk of dementia decreased by 23% in the pioglitazone-treated cohort compared with that in the comparison cohort after adjustment for age, sex, hypertension, and stroke (adjusted hazard ratio [HR], 0.77; 95% confidence interval [CI]=0.62-0.96). In addition, the adjusted HRs (95% CIs) for dementia were 0.50 (0.34-0.75, P=.001) in high-cumulative dose users, 0.53 (0.36-0.77, P<.001) in long-term users, and 0.66 (0.49-0.90, P=.009) in high-mean daily dose users. CONCLUSIONS: Pioglitazone is a time- and dose-dependent protective factor against dementia in patients with diabetes. The risk of dementia is lower in long-term and high-dose pioglitazone users than in never users of pioglitazone.
- 40Kummer, M. P.; Heneka, M. T. PPARs in Alzheimer’s Disease. PPAR Res. 2008, 2008, 403896, DOI: 10.1155/2008/403896[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cvmslWqtA%253D%253D&md5=6a54ae24b134f720094fab1c67e49e9cPPARs in Alzheimer's DiseaseKummer Markus P; Heneka Michael TPPAR research (2008), 2008 (), 403896 ISSN:1687-4757.Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the neurodegeneration and the deposition of the beta-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARgamma. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARgamma. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPARgamma receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD.
- 41Heneka, M. T.; Reyes-Irisarri, E.; Hull, M.; Kummer, M. P. Impact and Therapeutic Potential of PPARs in Alzheimers Disease. Curr. Neuropharmacol. 2011, 9 (4), 643– 650, DOI: 10.2174/157015911798376325[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFWhs74%253D&md5=4c6faf8a714bc696eb130266005b5b09Impact and therapeutic potential of PPARs in Alzheimer's diseaseHeneka, Michael T.; Reyes-Irisarri, Elisabet; Huell, Michael; Kummer, Markus P.Current Neuropharmacology (2011), 9 (4), 643-650CODEN: CNUEAN; ISSN:1875-6190. (Bentham Science Publishers Ltd.)A review. Peroxisome proliferator activated receptors (PPARs) are well studied for their role of peripheral metab., but they also may be involved in the pathogenesis of various disorders of the central nervous system (CNS) including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's and, Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases, lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the deposition of the β-amyloid peptide in extracellular plaques and ongoing neurodegeneration. Non-steroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD related transgenic cellular and animal models. Stimulation of PPARγ by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic and insulin sensitizing effects may account for the obsd. effects. Several clin. trials already revealed promising results using PPARγ agonists, therefore PPARγ represents an attractive therapeutic target for the treatment of AD.
- 42Du, J.; Zhang, L.; Liu, S.; Zhang, C.; Huang, X.; Li, J.; Zhao, N.; Wang, Z. PPARγ Transcriptionally Regulates the Expression of Insulin-Degrading Enzyme in Primary Neurons. Biochem. Biophys. Res. Commun. 2009, 383 (4), 485– 490, DOI: 10.1016/j.bbrc.2009.04.047[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXls1KhsLk%253D&md5=5aa4a9fd88960a81de738c22a74c61efPPARγ transcriptionally regulates the expression of insulin-degrading enzyme in primary neuronsDu, Jing; Zhang, Lang; Liu, Shubo; Zhang, Chi; Huang, Xiuqing; Li, Jian; Zhao, Nanming; Wang, ZhaoBiochemical and Biophysical Research Communications (2009), 383 (4), 485-490CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Insulin-degrading enzyme (IDE) is a protease that has been demonstrated to play a key role in degrading both Aβ and insulin and deficient in IDE function is assocd. with Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2) pathol. However, little is known about the cellular and mol. regulation of IDE expression. Here we show IDE levels are markedly decreased in DM2 patients and pos. correlated with the peroxisome proliferator-activated receptor γ (PPARγ) levels. Further studies show that PPARγ plays an important role in regulating IDE expression in rat primary neurons through binding to a functional peroxisome proliferator-response element (PPRE) in IDE promoter and promoting IDE gene transcription. Finally, we demonstrate that PPARγ participates in the insulin-induced IDE expression in neurons. These results suggest that PPARγ transcriptionally induces IDE expression which provides a novel mechanism for the use of PPARγ agonists in both DM2 and AD therapies.
- 43Quan, Q.; Qian, Y.; Li, X.; Li, M. Pioglitazone Reduces β Amyloid Levels via Inhibition of PPARγ Phosphorylation in a Neuronal Model of Alzheimer’s Disease. Front. Aging Neurosci. 2019, 11, 178, DOI: 10.3389/fnagi.2019.00178[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjs1yjur8%253D&md5=f459cb455831b4a9f07ae435f5dfdbb3Pioglitazone reduces β amyloid levels via inhibition of PPARγ phosphorylation in a neuronal model of Alzheimer's diseaseQuan, Qiankun; Qian, Yihua; Li, Xi; Li, MingFrontiers in Aging Neuroscience (2019), 11 (), 178CODEN: FANRC5; ISSN:1663-4365. (Frontiers Media S.A.)It has been demonstrated that peroxisome proliferator-activated receptor γ (PPARγ) can regulate the transcription of its target gene, insulin-degrading enzyme (IDE), and thus enhance the expression of the IDE protein. The protein can degrade β amyloid (Aβ), a core pathol. product of Alzheimer's disease (AD). PPARγ can also regulate the transcription of other target gene, β-amyloid cleavage enzyme 1 (BACE1), and thus inhibit the expression of the BACE1 protein. BACE1 can hydrolyze amyloid precursor protein (APP), the precursor of Aβ. In adipose tissue, PPARγ agonists can inhibit the phosphorylation of PPARγ by inhibiting cyclin-dependent kinase 5 (CDK5), which in turn affects the expression of target genes regulated by PPARγ. PPARγ agonists may also exert inhibitory effects on the phosphorylation of PPARγ in the brain, thereby affecting the expression of the aforementioned PPARγ target genes and reducing Aβ levels. The present study confirmed this hypothesis by showing that PPARγ agonist pioglitazone attenuated the neuronal apoptosis of primary rat hippocampal neurons induced by Aβ1-42, downregulated CDK5 expression, weakened the binding of CDK5 to PPARγ, reduced PPARγ phosphorylation, increased the expression of PPARγ and IDE, decreased the expression of BACE1, reduced APP prodn., and downregulated intraneuronal Aβ1-42 levels. These effects were inhibited by the PPARγ antagonist GW9662. After CDK5 silencing with CDK5 shRNA, the above effect of pioglitazone was not obsd., except when upregulating the expression of PPARγ in Aβ1-42 treated neurons. In conclusion, this study demonstrated that pioglitazone could inhibit the phosphorylation of PPARγ in vitro by inhibiting CDK5 expression, which in turn affected the expression of PPARγ target genes Ide and Bace1, thereby promoting Aβ degrdn. and reducing Aβ prodn. This reduced Aβ levels in the brain, thereby exerting neuroprotective effects in an AD model.
- 44Sastre, M.; Dewachter, I.; Rossner, S.; Bogdanovic, N.; Rosen, E.; Borghgraef, P.; Evert, B. O.; Dumitrescu-Ozimek, L.; Thal, D. R.; Landreth, G.; Walter, J.; Klockgether, T.; Van Leuven, F.; Heneka, M. T. Nonsteroidal Anti-Inflammatory Drugs Repress β-Secretase Gene Promoter Activity by the Activation of PPARγ. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (2), 443– 448, DOI: 10.1073/pnas.0503839103[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XpsVSluw%253D%253D&md5=ff887abb8a138a2539a859295887c0a3Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγSastre, Magdalena; Dewachter, Ilse; Rossner, Steffen; Bogdanovic, Nenad; Rosen, Evan; Borghgraef, Peter; Evert, Bernd O.; Dumitrescu-Ozimek, Lucia; Thal, Dietmar R.; Landreth, Gary; Walter, Jochen; Klockgether, Thomas; van Leuven, Fred; Heneka, Michael T.Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (2), 443-448CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Epidemiol. evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated receptor-γ (PPARγ), which is a nuclear transcriptional regulator. Here we show that PPARγ depletion potentiates β-secretase [β-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARγ, as well as NSAIDs and PPARγ activators, reduced BACE1 gene promoter activity. These results suggested that PPARγ could be a repressor of BACE1. We then identified a PPARγ responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARγ to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPARγ gene transcription, and this effect was suppressed by NSAIDs. We also demonstrate that in vivo treatment with PPARγ agonists increased PPARγ and reduced BACE1 mRNA and intracellular β-amyloid levels. Interestingly, brain exts. from AD patients showed decreased PPARγ expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPARγ in the modulation of amyloid-β generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPARγ and decreased BACE1 gene transcription.
- 45Sastre, M.; Dewachter, I.; Landreth, G. E.; Willson, T. M.; Klockgether, T.; Van Leuven, F.; Heneka, M. T. Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor-γ Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of β-Secretase. J. Neurosci. 2003, 23 (30), 9796– 9804, DOI: 10.1523/JNEUROSCI.23-30-09796.2003[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXovVKis7w%253D&md5=b7e010a3cc3774b7f42444da3a49324aNonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-γ agonists modulate immunostimulated processing of amyloid precursor protein through regulation of β-secretaseSastre, Magdalena; Dewachter, Ilse; Landreth, Gary E.; Willson, Timothy M.; Klockgether, Thomas; van Leuven, Fred; Heneka, Michael T.Journal of Neuroscience (2003), 23 (30), 9796-9804CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk for Alzheimer's disease (AD). To det. the mechanisms by which inflammation affects AD and how NSAIDs protect against it, we stimulated neuroblastoma cells stably transfected with amyloid precursor protein (APP) with proinflammatory cytokines, which increased the secretion of amyloid-β and APP ectodomain. Addn. of ibuprofen, indomethacin, peroxisome proliferator-activated receptor-γ (PPARγ) agonists, or cotransfection with PPARγ cDNA reversed this effect. The inhibitory action of ibuprofen and indomethacin was suppressed by PPARγ antagonists. Finally, we obsd. that the mRNA levels, expression, and enzymic activity of β-secretase were increased by immunostimulation and normalized by NSAIDs. In conclusion, proinflammatory cytokines activate β-secretase, and NSAIDs inhibit this effect through PPARγ.
- 46Yang, S.; Chen, Z.; Cao, M.; Li, R.; Wang, Z.; Zhang, M. Pioglitazone Ameliorates Aβ42 Deposition in Rats with Diet-Induced Insulin Resistance Associated with AKT/GSK3β Activation. Mol. Med. Rep. 2017, 15 (5), 2588– 2594, DOI: 10.3892/mmr.2017.6342[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFWktrbN&md5=709e610125cc5179b3b340951ea31696Pioglitazone ameliorates Aβ42 deposition in rats with diet-induced insulin resistance associated with AKT/GSK3β activationYang, Sisi; Chen, Zhe; Cao, Ming; Li, Renjie; Wang, Zhigang; Zhang, MuxunMolecular Medicine Reports (2017), 15 (5), 2588-2594CODEN: MMROA5; ISSN:1791-3004. (Spandidos Publications Ltd.)Pioglitazone may have potential benefits as an alternative therapeutic treatment for patients with Alzheimer's disease (AD), particularly in individuals that also have comorbid diabetes; however, the mechanisms of action remain unclear. The present study aimed to explore the effects of pioglitazone on amyloid β, isoform 42 (Aβ42) deposition in rats with diet-induced insulin resistance (IR). Diet-induced IR model rats were established in the presence or absence of pioglitazone. Plasma glucose and insulin levels, and cerebrospinal fluid insulin levels were measured; in addn., hippocampal tissues were collected for immunohistochem. anal. of Aβ42 expression. The levels of insulin-degrading enzyme (IDE) and peroxisome proliferator-activated receptor γ (PPARγ) mRNA and protein expression were analyzed by reverse transcription-quant. polymerase chain reaction and western blotting, resp. In addn., the activation of glycogen synthase kinase 3β (GSK3β) induced by phosphatidylinositol 3-kinase (PI3K) /protein kinase B (AKT) signaling was detected by western blotting. Results from the present study demonstrated that pioglitazone may enhance peripheral and brain insulin sensitivity in diet-induced IR model rats. Treatment with pioglitazone ameliorated Aβ42 deposition in the hippocampus by increasing IDE and PPARγ expression. Notably, activation of the PI3K/AKT/GSK3β pathway was also demonstrated to serve a role in pioglitazone-induced Aβ42 degrdn., which was abrogated by the PPARγ antagonist GW9662. Results from the present study indicated that pioglitazone may improve insulin sensitivity and ameliorate Aβ42 accumulation in rats with diet-induced IR by regulating AKT/GSK3β activation, suggesting that pioglitazone may be a promising drug for AD treatment.
- 47Chang, K. L.; Wong, L. R.; Pee, H. N.; Yang, S.; Ho, P. C. L. Reverting Metabolic Dysfunction in Cortex and Cerebellum of APP/PS1Mice, a Model for Alzheimer’s Disease by Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist. Mol. Neurobiol. 2019, 56 (11), 7267– 7283, DOI: 10.1007/s12035-019-1586-2[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXosF2qu74%253D&md5=22df1faf51285ab5c7074da6312d564fReverting Metabolic Dysfunction in Cortex and Cerebellum of APP/PS1 Mice, a Model for Alzheimer's Disease by Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma) AgonistChang, Kai Lun; Wong, Ling Rong; Pee, Hai Ning; Yang, Shili; Ho, Paul Chi-LuiMolecular Neurobiology (2019), 56 (11), 7267-7283CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Identification of mol. mechanisms underlying early-stage Alzheimer's disease (AD) is important for the development of new therapies against and diagnosis of AD. In this study, gas chromatog. time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics approach was employed to investigate the metabolic profiles in plasma and brain tissues harvested from 5-mo-old APP/PS1 transgenic mice and their wildtype counterparts. Since different brain regions were expected to have their own distinct metabolic signals, four different brain regions, namely cortex, hippocampus, midbrain and cerebellum tissues, were dissected and had their metabolic profiles studied sep. Biochem. assays were also performed on plasma and brain cortex tissue of transgenic mice and wildtype mice, with a focus on mitochondrial health. Our findings include the observation of extensive metabolic alterations in cortex and cerebellum of APP/PS1 mice, but not in their hippocampus, midbrain and plasma. The major pathways affected in cortex and cerebellum of APP/PS1 mice were closely related to impaired energy metab. and perturbation of amino acid metab. in these mice. Treatment with the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist pioglitazone (PIO) successfully restored the energy metab., lowered amyloid-beta levels and afforded the APP/PS1 mice a better antioxidative capacity in their cortex.
- 48Yu, Y.; Li, X.; Blanchard, J.; Li, Y.; Iqbal, K.; Liu, F.; Gong, C.-X. Insulin Sensitizers Improve Learning and Attenuate Tau Hyperphosphorylation and Neuroinflammation in 3xTg-AD Mice. J. Neural Transm. 2015, 122 (4), 593– 606, DOI: 10.1007/s00702-014-1294-z[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlamsbbI&md5=5ecc0beb6f4f83df2022e50a82a280d1Insulin sensitizers improve learning and attenuate tau hyperphosphorylation and neuroinflammation in 3xTg-AD miceYu, Yang; Li, Xiaojing; Blanchard, Julie; Li, Yi; Iqbal, Khalid; Liu, Fei; Gong, Cheng-XinJournal of Neural Transmission (2015), 122 (4), 593-606CODEN: JNTRF3; ISSN:0300-9564. (Springer-Verlag GmbH)A review. Sporadic Alzheimer's disease (AD) is a multifactorial metabolic brain disorder characterized by progressive neurodegeneration. Decreased brain energy and glucose metab. occurs before the appearance of AD symptoms and worsens while the disease progresses. Deregulated brain insulin signaling has also been found in AD recently. To restore brain insulin sensitivity and glucose metab., pioglitazone and rosiglitazone, two insulin sensitizers commonly used for treating type 2 diabetes, have been studied and shown to have some beneficial effects in AD mouse models. However, the mol. mechanisms of the beneficial effects remain elusive. In the present study, we treated the 3xTg-AD mice, a widely used mouse model of AD, with pioglitazone and rosiglitazone for 4 mo and studied the effects of the treatments on cognitive performance and AD-related brain alterations. We found that the chronic treatment improved spatial learning, enhanced AKT signaling, and attenuated tau hyperphosphorylation and neuroinflammation. These findings shed new light on the possible mechanisms by which these two insulin sensitizers might be useful for treating AD and support further clin. trials evaluating the efficacy of these drugs.
- 49Du, J.; Sun, B.; Chen, K.; Fan, L.; Wang, Z. Antagonist of Peroxisome Proliferator-Activated Receptor γ Induces Cerebellar Amyloid-β Levels and Motor Dysfunction in APP/PS1 Transgenic Mice. Biochem. Biophys. Res. Commun. 2009, 384 (3), 357– 361, DOI: 10.1016/j.bbrc.2009.04.148[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmsVCqsro%253D&md5=a1354eb3b803c5aba1cb82a3764569f0Antagonist of peroxisome proliferator-activated receptor γ induces cerebellar amyloid-β levels and motor dysfunction in APP/PS1 transgenic miceDu, Jing; Sun, Bing; Chen, Kui; Fan, Li; Wang, ZhaoBiochemical and Biophysical Research Communications (2009), 384 (3), 357-361CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Recent evidences show that peroxisome proliferator-activated receptor γ (PPARγ) is involved in the modulation of the amyloid-β (Aβ) cascade causing Alzheimer's disease (AD) and treatment with PPARγ agonists protects against AD pathol. However, the function of PPARγ steady-state activity in Aβ cascade and AD pathol. remains unclear. In this study, an antagonist of PPARγ, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPARγ activity in cerebellum. The results show that inhibition of PPARγ significantly induced Aβ levels in cerebellum and caused cerebellar motor dysfunction in APP/PS1 transgenic mice. Moreover, GW9662 treatment markedly decreased the cerebellar levels of insulin-degrading enzyme (IDE), which is responsible for the cellular degrdn. of Aβ. Since cerebellum is spared from significant Aβ accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPARγ steady-state activity in protection of cerebellum against AD pathol.
- 50Fernandez-Martos, C. M.; Atkinson, R. A. K.; Chuah, M. I.; King, A. E.; Vickers, J. C. Combination Treatment with Leptin and Pioglitazone in a Mouse Model of Alzheimer’s Disease. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2017, 3 (1), 92– 106, DOI: 10.1016/j.trci.2016.11.002
- 51Chen, J.; Li, S.; Sun, W.; Li, J. Anti-Diabetes Drug Pioglitazone Ameliorates Synaptic Defects in AD Transgenic Mice by Inhibiting Cyclin-Dependent Kinase5 Activity. PLoS One 2015, 10, e0123864 DOI: 10.1371/journal.pone.0123864[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslCrs7zO&md5=a359296d8fc981800214658afd5064e3Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activityChen, Jinan; Li, Shenghua; Sun, Wenshan; Li, JunrongPLoS One (2015), 10 (4), e0123864/1-e0123864/12CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is activated by the neuron specific activators p35/p39 and plays many important roles in neuronal development. However, aberrant activation of Cdk5 is believed to be assocd. with the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Here in the present study, enhanced Cdk5 activity was obsd. in mouse models of AD; whereas sol. amyloid-β oligomers (Aβ), which contribute to synaptic failures during AD pathogenesis, induced Cdk5 hyperactivation in cultured hippocampal neurons. Inhibition of Cdk5 activity by pharmacol. or genetic approaches reversed dendritic spine loss caused by sol. amyloid-β oligomers (Aβ) treatment. Interestingly, we found that the anti-diabetes drug pioglitazone could inhibit Cdk5 activity by decreasing p35 protein level. More importantly, pioglitazone treatment cor. long-term potentiation (LTP) deficit caused by Aβ exposure in cultured slices and pioglitazone administration rescued impaired LTP and spatial memory in AD mouse models. Taken together, our study describes an unanticipated role of pioglitazone in alleviating AD and reveals a potential therapeutic drug for AD curing.
- 52Mandrekar-Colucci, S.; Karlo, J. C.; Landreth, G. E. Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer’s Disease. J. Neurosci. 2012, 32 (30), 10117– 10128, DOI: 10.1523/JNEUROSCI.5268-11.2012[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFart7%252FL&md5=20dfa3dc6ded1b482798a7f33ed60dd6Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's diseaseMandrekar-Colucci, Shweta; Karlo, J. Colleen; Landreth, Gary E.Journal of Neuroscience (2012), 32 (30), 10117-10128CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Alzheimer's disease is assocd. with a disruption of amyloid β (Aβ) homeostasis, resulting in the accumulation and subsequent deposition of Aβ peptides within the brain. The peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor that acts in a coupled metabolic cycle with Liver X Receptors (LXRs) to increase brain apolipoprotein E (apoE) levels. ApoE functions to promote the proteolytic clearance of sol. forms of Aβ, and we found that the synthetic PPARγ agonist, pioglitazone, stimulated Aβ degrdn. by both microglia and astrocytes in an LXR and apoE-dependent manner. Remarkably, a brief 9 d oral treatment of APPswe/PS1Δe9 mice with pioglitazone resulted in dramatic redns. in brain levels of sol. and insol. Aβ levels which correlated with the loss of both diffuse and dense-core plaques within the cortex. The removal of preexisting amyloid deposits was assocd. with the appearance of abundant Aβ-laden microglia and astrocytes. Pioglitazone treatment resulted in the phenotypic polarization of microglial cells from a proinflammatory M1 state, into an anti-inflammatory M2 state that was assocd. with enhanced phagocytosis of deposited forms of amyloid. The redn. in amyloid levels was assocd. with a reversal of contextual memory deficits in the drug-treated mice. These data provide a mechanistic explanation for how PPARγ activation facilitates amyloid clearance and supports the therapeutic utility of PPARγ agonists for the treatment of Alzheimer's disease.
- 53Papadopoulos, P.; Rosa-Neto, P.; Rochford, J.; Hamel, E. Pioglitazone Improves Reversal Learning and Exerts Mixed Cerebrovascular Effects in a Mouse Model of Alzheimer’s Disease with Combined Amyloid-β and Cerebrovascular Pathology. PLoS One 2013, 8 (7), e68612, DOI: 10.1371/journal.pone.0068612[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1WmtL7E&md5=fce388f68d0ca9c987ba06ea9172aa10Pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer's disease with combined amyloid-β and cerebrovascular pathologyPapadopoulos, Panayiota; Rosa-Neto, Pedro; Rochford, Joseph; Hamel, EdithPLoS One (2013), 8 (7), e68612CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Animal models of Alzheimer's disease (AD) are invaluable in dissecting the pathogenic mechanisms and assessing the efficacy of potential new therapies. Here, we used the peroxisome proliferator-activated receptor gamma agonist pioglitazone in an attempt to rescue the pathogenic phenotype in adult (12 mo) and aged (>18 mo) bitransgenic A/T mice that overexpress a mutated human amyloid precursor protein (APPSwe,Ind) and a constitutively active form of transforming growth factor-β1 (TGF-β1). A/T mice recapitulate the AD-related cognitive deficits, amyloid beta (Aβ) and cerebrovascular pathologies, as well as the altered metabolic and vascular coupling responses to increased neuronal activity. Pioglitazone normalized neurometabolic and neurovascular coupling responses to sensory stimulation, and reduced cortical astroglial and hippocampal microglial activation in both age groups. Spatial learning and memory deficits in the Morris water maze were not rescued by pioglitazone, but reversal learning was improved in the adult cohort notwithstanding a progressing Aβ pathol. While pioglitazone preserved the constitutive nitric oxide synthesis in the vessel wall, it unexpectedly failed to restore cerebrovascular reactivity in A/T mice and even exacerbated the dilatory deficits. These data demonstrate pioglitazone's efficacy on selective AD hallmarks in a complex AD mouse model of comorbid amyloidosis and cerebrovascular pathol. They further suggest a potential benefit of pioglitazone in managing neuroinflammation, cerebral perfusion and glucose metab. in AD patients devoid of cerebrovascular pathol.
- 54Prakash, A.; Kumar, A. Role of Nuclear Receptor on Regulation of BDNF and Neuroinflammation in Hippocampus of β-Amyloid Animal Model of Alzheimer’s Disease. Neurotoxic. Res. 2014, 25 (5), 335– 347, DOI: 10.1007/s12640-013-9437-9[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXls12qsrk%253D&md5=54ca948f8ec0066c16c42dd0015f1e04Role of Nuclear Receptor on Regulation of BDNF and Neuroinflammation in Hippocampus of β-Amyloid Animal Model of Alzheimer's DiseasePrakash, Atish; Kumar, AnilNeurotoxicity Research (2014), 25 (4), 335-347CODEN: NURRFI; ISSN:1029-8428. (Springer)Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have been reported to provide neuroprotective effects against neurodegenerative diseases. The current study was carried out to investigate the effects of chronic administration of pioglitazone, a PPAR-γ agonist, on cognitive impairment in an animal model of Alzheimer's disease induced by β-amyloid. Wistar rats received intracerebroventricular (ICV) β-amyloid (βA) application (3 nmol/3 μL), and behavioral alterations (locomotor activity and memory performance) were assessed. Animals were sacrificed immediately following the last behavioral session, and their brains were removed and dissected. Mitochondrial enzymes, oxidative parameters, inflammatory mediators (TNF-α, IL-6), caspase activity, and BDNF levels were measured in the hippocampus. ICV βA-treated rats showed a memory deficit and significantly decreased BDNF level, simultaneously, increase in mitochondrial oxidative damage and inflammatory mediators in the hippocampus. Memory impairment and oxidative damage were reversed by administration of pioglitazone (15 and 30 mg/kg). Pioglitazone also significantly restored the BDNF level and attenuated the actions of inflammatory markers in ICV βA-treated rats. However, pretreatment with PPAR-γ antagonist BADGE (15 mg/kg) with higher dose of pioglitazone significantly reversed its protective action in memory impairment in βA-treated rats, which indicates the involvement of PPAR-γ receptors mediating neuroprotective action. These results demonstrate that pioglitazone offers protection against β-amyloid-induced memory dysfunction possibly due to its antioxidant, anti-inflammatory, anti-apoptotic action and neurogenesis-like effect therefore, could have a therapeutic potential in Alzheimer's disease.
- 55Hamano, T.; Shirafuji, N.; Makino, C.; Yen, S.-H.; Kanaan, N. M.; Ueno, A.; Suzuki, J.; Ikawa, M.; Matsunaga, A.; Yamamura, O.; Kuriyama, M.; Nakamoto, Y. Pioglitazone Prevents Tau Oligomerization. Biochem. Biophys. Res. Commun. 2016, 478 (3), 1035– 1042, DOI: 10.1016/j.bbrc.2016.08.016[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVWmsb%252FP&md5=f81bd55b047a6ad500b9d0ca9f391668Pioglitazone prevents tau oligomerizationHamano, Tadanori; Shirafuji, Norimichi; Makino, Chiemi; Yen, Shu-Hui; Kanaan, Nicholas M.; Ueno, Asako; Suzuki, Jinya; Ikawa, Masamichi; Matsunaga, Akiko; Yamamura, Osamu; Kuriyama, Masaru; Nakamoto, YasunariBiochemical and Biophysical Research Communications (2016), 478 (3), 1035-1042CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Tau aggregation and amyloid β protein (Aβ) deposition are the main causes of Alzheimer's disease (AD). Peroxisome proliferator-activated receptor γ (PPARγ) activation modulates Aβ prodn. To test whether the PPARγ agonist pioglitazone (PIO) is also effective in preventing tau aggregation in AD, we used a cellular model in which wild-type tau protein (4R0N) is overexpressed (M1C cells) (Hamano et al., 2012) as well as primary neuronal cultures. PIO reduced both phosphorylated and total tau levels, and inactivated glycogen synthase kinase 3β, a major tau kinase, assocd. with activation of Akt. In addn., PIO decreased cleaved caspase3 and C-terminal truncated tau species by caspase, which is expected to decrease tau aggregation. A fractionation study showed that PIO reduced high mol.-wt. (120 kDa), oligomeric tau species in Tris Insol., sarkosyl-sol. fractions. Tau decrease was reversed by adding GW9662, a PPARγ antagonist. Together, our current results support the idea that PPARγ agonists may be useful therapeutic agents for AD.
- 56Cho, D.-H.; Lee, E. J.; Kwon, K. J.; Shin, C. Y.; Song, K.-H.; Park, J.-H.; Jo, I.; Han, S.-H. Troglitazone, a Thiazolidinedione, Decreases Tau Phosphorylation through the Inhibition of Cyclin-Dependent Kinase 5 Activity in SH-SY5Y Neuroblastoma Cells and Primary Neurons. J. Neurochem. 2013, 126 (5), 685– 695, DOI: 10.1111/jnc.12264[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlSqu77E&md5=bc41a6c9ecae5a8ab3982eecd77b09bbTroglitazone, a thiazolidinedione, decreases tau phosphorylation through the inhibition of cyclin-dependent kinase 5 activity in SH-SY5Y neuroblastoma cells and primary neuronsCho, Du-Hyong; Lee, Eun Joo; Kwon, Kyoung Ja; Shin, Chan Young; Song, Kee-Ho; Park, Jung-Hyun; Jo, Inho; Han, Seol-HeuiJournal of Neurochemistry (2013), 126 (5&6), 685-695CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)The peroxisome proliferator-activated receptor gamma (PPARγ) agonists thiazolidinediones (TZDs) are prescribed for the treatment of type 2 diabetes mellitus. Furthermore, it has been reported that TZDs have a beneficial effect on neurodegenerative disorders, such as Alzheimer's disease. However, the mol. mechanisms underlying this effect are not fully understood. Here, we investigated whether and how troglitazone, a parent TZD drug, inhibits tau phosphorylation. Treatment with troglitazone decreased tau-Thr231 phosphorylation and p35, the specific activator of cyclin-dependent kinase 5 (CDK5), in a dose- and time-dependent manner. Troglitazone also decreased CDK5 enzymic activity, and ectopic expression of p25, the cleaved and more active form of p35, restored the troglitazone-induced decrease in tau-Thr231 phosphorylation. Treatment with either MG-132, a reversible proteasome inhibitor, or lactacystin, a specific and irreversible 26S proteasome inhibitor, significantly reversed the obsd. inhibitory effects of troglitazone. However, GW9662, a specific and irreversible PPARγ antagonist, did not alter the obsd. inhibitory effects. Similar results were also found when other TZD drugs, pioglitazone and rosiglitazone, were used. Treatment with various inhibitors revealed that troglitazone-induced inhibitions of tau-Thr231 phosphorylation and p35 expression were not mediated by glycogen synthase kinase 3β, protein kinase A, and protein phosphatase 2A signaling pathways. Finally, we also found that the same obsd. inhibitory effects of troglitazone hold true for the use of primary cortical neurons. Taken together, we demonstrated that TZDs repressed tau-Thr231 phosphorylation via the inhibition of CDK5 activity, which was mediated by the proteasomal degrdn. of p35 and a PPARγ-independent signaling pathway. Thiazolidinediones (TZDs) decrease tau-Thr231 phosphorylation via the inhibition of CDK5 enzymic activity, which is mediated by the enhanced proteasomal degrdn. of p35 and a PPARγ-independent signaling pathway. This mol. mechanism implies a role for TZD drugs in the prevention and treatment of Alzheimer's disease.
- 57Harrington, C.; Sawchak, S.; Chiang, C.; Davies, J.; Donovan, C.; Saunders, A. M.; Irizarry, M.; Jeter, B.; Zvartau-Hind, M.; H. van Dyck, C.; Gold, M. Rosiglitazone Does Not Improve Cognition or Global Function When Used as Adjunctive Therapy to AChE Inhibitors in Mild-to-Moderate Alzheimers Disease: Two Phase 3 Studies. Curr. Alzheimer Res. 2011, 8 (5), 592– 606, DOI: 10.2174/156720511796391935[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsl2qtrw%253D&md5=54516c366701851a6d1745fc07969108Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studiesHarrington, C.; Sawchak, S.; Chiang, C.; Davies, J.; Donovan, C.; Saunders, A. M.; Irizarry, M.; Jeter, B.; Zvartau-Hind, M.; van Dyck, C. H.; Gold, M.Current Alzheimer Research (2011), 8 (5), 592-606CODEN: CARUBY; ISSN:1567-2050. (Bentham Science Publishers Ltd.)Introduction: Two phase 3 studies evaluated the efficacy and safety of rosiglitazone (RSG), a type 2 diabetes treatment, in an extended release (RSG XR) form as adjunctive therapy to ongoing acetylcholine esterase inhibitor (AChEI) treatment in AD (REFLECT-2, adjunctive to donepezil; REFLECT-3, to any AChEI). An open-label extension study (REFLECT-4) assessed RSG XR long-term safety. Methods: In these two double-blind, placebo-controlled studies, subjects with mild-to-moderate probable AD were randomized within 2 apolipoprotein E (APOE) allelic strata (APOE ε4-pos., APOE ε4-neg.) to once daily placebo, 2 mg RSG XR, or 8 mg RSG XR for 48 wk (REFLECT-2, N = 1,496; REFLECT-3, N = 1,485). Co-primary efficacy endpoints were change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Clin. Dementia Rating scale - Sum of Boxes (CDR-SB) scores at week 48. Three populations were analyzed: APOE4-neg., all subjects except APOE ε4 homozygotes, and the full intent-to-treat population. Results: No statistically or clin. relevant differences between treatment groups were obsd. on the a priori primary endpoints in REFLECT-2 or REFLECT-3. Edema was the most frequent adverse event with RSG in each study (14% and 19%, resp., at 8 mg RSG XR). Conclusions: No evidence of statistically or clin. significant efficacy in cognition or global function was detected for 2 mg or 8 mg RSG XR as adjunctive therapy to ongoing AChEIs. There was no evidence of an interaction between treatment and APOE status. Safety and tolerability of RSG XR was consistent with the known profile of rosiglitazone.
- 58Gold, M.; Alderton, C.; Zvartau-Hind, M.; Egginton, S.; Saunders, A. M.; Irizarry, M.; Craft, S.; Landreth, G.; Linnamägi, Ü.; Sawchak, S. Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer’s Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III Study. Dementia Geriatr. Cognit. Disord. 2010, 30 (2), 131– 146, DOI: 10.1159/000318845[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1agsrjM&md5=22e08bf51f12957b0f1508fdef931470Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer's Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III StudyGold, Michael; Alderton, Claire; Zvartau-Hind, Marina; Egginton, Sally; Saunders, Ann M.; Irizarry, Michael; Craft, Suzanne; Landreth, Gary; Linnamaegi, Uella; Sawchak, SharonDementia and Geriatric Cognitive Disorders (2010), 30 (2), 131-146CODEN: DGCDFX; ISSN:1420-8008. (S. Karger AG)A phase II study of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer's disease (AD) detected a treatment benefit to cognition in apolipoprotein E(APOE)-ε4-neg. subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR. This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (ε4-pos., ε4-neg.), subjects were randomized (2:2:2:1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+). At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-ε4-neg. subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%). No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-ε4-neg. or other anal. populations. The safety and tolerability of RSG XR was consistent with its known pharmacol.
- 59Cheng, H.; Shang, Y.; Jiang, L.; Shi, T.-L.; Wang, L. The Peroxisome Proliferators Activated Receptor-Gamma Agonists as Therapeutics for the Treatment of Alzheimer’s Disease and Mild-to-Moderate Alzheimer’s Disease: A Meta-Analysis. Int. J. Neurosci. 2016, 126 (4), 299– 307, DOI: 10.3109/00207454.2015.1015722[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht12qsrw%253D&md5=78879ad4a62f4a65543c438a46228e11The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysisCheng, Huawei; Shang, Yuping; Jiang, Ling; Shi, Tian-lu; Wang, LinInternational Journal of Neuroscience (2016), 126 (4), 299-307CODEN: IJNUB7; ISSN:0020-7454. (Taylor & Francis Ltd.)Alzheimer's disease (AD) is a devastating neurodegenerative disease and there is no effective therapy for it. Peroxisome proliferators activated receptor-gamma (PPAR-γ) agonists is a promising therapeutic approach for AD and has been widely studied recently, but no consensus was available up to now. To clarify this point, a meta-anal. was performed. We searched MEDLINE, EMBASE, Cochrane Central database, PUBMED, Springer Link database, SDOS database, CBM, CNKI and Wan fang database by Dec. 2014. Standardized mean difference (SMD), relative risk (RR) and 95% confidence interval (CI) were calcd. to assess the strength of the novel therapeutics for AD and mild-to-moderate AD. A total of nine studies comprising 1314 patients and 1311 controls were included in the final meta-anal. We found the effect of PPAR-γ agonists on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) scores by using STATA software. There was no evidence for obvious publication bias in the overall meta-anal. There is insufficient evidence of statistically incognition of AD and mild-to-moderate AD patients have been improved who were treated with PPAR-γ agonists in our research. However, PPAR-γ agonists may be a promising therapeutic approach in future, esp. pioglitazone, with large-scale randomized controlled trials to confirm.
- 60Liu, J.; Wang, L.; Jia, J. Peroxisome Proliferator-Activated Receptor-Gamma Agonists for Alzheimer’s Disease and Amnestic Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. Drugs Aging 2015, 32 (1), 57– 65, DOI: 10.1007/s40266-014-0228-7[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitV2ntL3E&md5=bc3fcbb735e4ea8c63ec912d0ee4dfc1Peroxisome Proliferator-Activated Receptor-Gamma Agonists for Alzheimer's Disease and Amnestic Mild Cognitive Impairment: A Systematic Review and Meta-AnalysisLiu, Jia; Wang, Lu-ning; Jia, Jian-pingDrugs & Aging (2015), 32 (1), 57-65CODEN: DRAGE6; ISSN:1170-229X. (Springer International Publishing AG)Background: Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, and close assocns. between AD and diabetes have been found. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists, as newly-developed oral hypoglycemic agents, were evaluated as a possible therapy for AD. Aim: We systematically evaluated the efficacy and safety of PPAR-γ agonists in the treatment of AD and amnestic mild cognitive impairment (aMCI), the prodromal stage of AD. Methods: A search of the electronic databases PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure (until July 2014) was conducted, and included randomized controlled trials. Dichotomous data were expressed as risk ratios (RRs) with 95 % confidence intervals (CIs), and continuous data were expressed as mean differences (MD) with 95 % CIs. The results were pooled using a random-effects model. Results: Nine eligible studies were identified, with 4,327 participants. Using the Alzheimer's Disease Assessment Scale-Cognitive subscale, pioglitazone was found to be efficacious, esp. for patients with comorbid diabetes (MD -3.47, 95 % CI -4.40 to -2.54). Rosiglitazone was not efficacious, even for apolipoprotein E (APOE) ε4 non-carriers (MD -0.31, 95 % CI -1.12 to 0.51). There was no increase in any adverse events (AEs) or serious AEs compared with placebo. Peripheral edema was the most frequent AE related to PPAR-γ agonist treatment (RR 4.14, 95 % CI 2.37-7.23). Conclusions: There is insufficient evidence to support the use of rosiglitazone in aMCI and AD patients in order to improve cognitive performance. Nonetheless, the efficacy of pioglitazone seems to be promising, particularly for patients with comorbid diabetes, however this needs to be further confirmed by well-designed trials with large sample sizes. PPAR-γ agonists such as rosiglitazone and pioglitazone are generally well-tolerated in AD and aMCI patients.
- 61Breidert, T.; Callebert, J.; Heneka, M. T.; Landreth, G.; Launay, J. M.; Hirsch, E. C. Protective Action of the Peroxisome Proliferator-Activated Receptor-γ Agonist Pioglitazone in a Mouse Model of Parkinson’s Disease. J. Neurochem. 2002, 82 (3), 615– 624, DOI: 10.1046/j.1471-4159.2002.00990.x[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xmt1ejsLY%253D&md5=a22e5318aae06a24540500bf18daa09fProtective action of the peroxisome proliferator-activated receptor-γ agonist pioglitazone in a mouse model of Parkinson's diseaseBreidert, T.; Callebert, J.; Heneka, M. T.; Landreth, G.; Launay, J. M.; Hirsch, E. C.Journal of Neurochemistry (2002), 82 (3), 615-624CODEN: JONRA9; ISSN:0022-3042. (Blackwell Science Ltd.)We examd. the effect of pioglitazone, a peroxisome proliferator-activated receptor-γ (PPARγ) agonist of the thiazolidinedione class, on dopaminergic nerve cell death and glial activation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. The acute intoxication of C57BL/6 mice with MPTP led to nigrostriatal injury, as detd. by tyrosine hydroxylase (TH) immunocytochem., and HPLC detection of striatal dopamine and metabolites. Damage to the nigrostriatal dopamine system was accompanied by a transient activation of microglia, as detd. by macrophage antigen-1 (Mac-1) and inducible nitric oxide synthase (iNOS) immunoreactivity, and a prolonged astrocytic response. Orally administered pioglitazone (∼ 20 mg/kg/day) attenuated the MPTP-induced glial activation and prevented the dopaminergic cell loss in the substantia nigra pars compacta (SNpc). In contrast, there was little redn. of MPTP-induced dopamine depletion, with no detectable effect on loss of TH immunoreactivity and glial response in the striatum of pioglitazone-treated animals. Low levels of PPARγ expression were detected in the ventral mesencephalon and striatum, and were unaffected by MPTP or pioglitazone treatment. Since pioglitazone affects primarily the SNpc in our model, different PPARγ-independent mechanisms may regulate glial activation in the dopaminergic terminals compared with the dopaminergic cell bodies after acute MPTP intoxication.
- 62Quinn, L. P.; Crook, B.; Hows, M. E.; Vidgeon-Hart, M.; Chapman, H.; Upton, N.; Medhurst, A. D.; Virley, D. J. The PPARγ Agonist Pioglitazone Is Effective in the MPTP Mouse Model of Parkinson’s Disease through Inhibition of Monoamine Oxidase B. Br. J. Pharmacol. 2008, 154 (1), 226– 233, DOI: 10.1038/bjp.2008.78[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXltFOqs7k%253D&md5=26608de37ec831814c50f23b1baa2b68The PPARγ agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase BQuinn, L. P.; Crook, B.; Hows, M. E.; Vidgeon-Hart, M.; Chapman, H.; Upton, N.; Medhurst, A. D.; Virley, D. J.British Journal of Pharmacology (2008), 154 (1), 226-233CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)The peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone has previously been shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease, an effect attributed to its anti-inflammatory properties. In the present investigation, we provide evidence that pioglitazone is effective in the MPTP mouse model, not via an anti-inflammatory action, but through inhibition of MAO-B, the enzyme required to biotransform MPTP to its active neurotoxic metabolite 1-methyl-4-phenylpyridinium (MPP+). Exptl. approach: Mice were treated with pioglitazone (20 mg kg-1 b.i.d. (twice a day), p.o., for 7 days), prior and post or post-MPTP (30 mg kg-1 s.c.) treatment. Mice were then assessed for motor impairments on a beam-walking app. and for redns. in TH immunoreactivity in the substantia nigra and depletions in striatal dopamine. The effects of pioglitazone on striatal MPP+ levels and MAO-B activity were also assessed. Mice treated with MPTP showed deficits in motor performance, marked depletions in striatal dopamine levels and a concomitant redn. in TH immunoreactivity in the substantia nigra. Pretreatment with pioglitazone completely prevented these effects of MPTP. However, pretreatment with pioglitazone also significantly inhibited the MPTP-induced prodn. of striatal MPP+ and the activity of MAO-B in the striatum. The neuroprotection obsd. with pioglitazone pretreatment in the MPTP mouse model was due to the blockade of the conversion of MPTP to its active toxic metabolite MPP+, via inhibition of MAO-B. Published online 10 March 2008.
- 63Pisanu, A.; Lecca, D.; Mulas, G.; Wardas, J.; Simbula, G.; Spiga, S.; Carta, A. R. Dynamic Changes in Pro-and Anti-Inflammatory Cytokines in Microglia after PPAR-γ Agonist Neuroprotective Treatment in the MPTPp Mouse Model of Progressive Parkinson’s Disease. Neurobiol. Dis. 2014, 71, 280– 291, DOI: 10.1016/j.nbd.2014.08.011[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVSqt73F&md5=5d178467ad1349b135b7328726844d92Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson's diseasePisanu, Augusta; Lecca, Daniela; Mulas, Giovanna; Wardas, Jadwiga; Simbula, Gabriella; Spiga, Saturnino; Carta, Anna R.Neurobiology of Disease (2014), 71 (), 280-291CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)Neuroinflammatory changes play a pivotal role in the progression of Parkinson's disease (PD) pathogenesis. Recent findings have suggested that activated microglia may polarize similarly to peripheral macrophages in the central nervous system (CNS), assuming a pro-inflammatory M1 phenotype or the alternative anti-inflammatory M2 phenotype via cytokine prodn. A skewed M1 activation over M2 has been related to disease progression in Alzheimer disease, and modulation of microglia polarization may be a therapeutic target for neuroprotection. By using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-probenecid (MPTPp) mouse model of progressive PD, we investigated dynamic changes in the prodn. of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and anti-inflammatory cytokines, such as transforming growth factor (TGF)-β and IL-10, within Iba-1-pos. cells in the substantia nigra compacta (SNc). In addn., to further characterize changes in the M2 phenotype, we measured CD206 in microglia. Moreover, in order to target microglia polarization, we evaluated the effect of the peroxisome-proliferator-activated receptor (PPAR)-γ agonist rosiglitazone, which has been shown to exert neuroprotective effects on nigral dopaminergic neurons in PD models, and acts as a modulator of cytokine prodn. and phenotype in peripheral macrophages.Chronic treatment with MPTPp induced a progressive degeneration of SNc neurons. The neurotoxin treatment was assocd. with a gradual increase in both TNF-α and IL-1β colocalization with Iba-1-pos. cells, suggesting an increase in pro-inflammatory microglia. In contrast, TGF-β colocalization was reduced by the neurotoxin treatment, while IL-10 was mostly unchanged. Administration of rosiglitazone during the full duration of MPTPp treatment reverted both TNF-α and IL-1β colocalization with Iba-1 to control levels. Moreover, rosiglitazone induced an increase in TGF-β and IL-10 colocalization compared with the MPTPp treatment. CD206 was gradually reduced by the chronic MPTPp treatment, while rosiglitazone restored control levels, suggesting that M2 anti-inflammatory microglia were stimulated and inflammatory microglia were inhibited by the neuroprotective treatment. The results show that the dopaminergic degeneration was assocd. with a gradual microglia polarization to the inflammatory over the anti-inflammatory phenotype in a chronic mouse model of PD. Neuroprotective treatment with rosiglitazone modulated microglia polarization, boosting the M2 over the pro-inflammatory phenotype. PPAR-γ agonists may offer a novel approach to neuroprotection, acting as disease-modifying drugs through an immunomodulatory action in the CNS.
- 64Swanson, C. R.; Joers, V.; Bondarenko, V.; Brunner, K.; Simmons, H. A.; Ziegler, T. E.; Kemnitz, J. W.; Johnson, J. A.; Emborg, M. E. The PPAR-γ Agonist Pioglitazone Modulates Inflammation and Induces Neuroprotection in Parkinsonian Monkeys. J. Neuroinflammation 2011, 8, 91, DOI: 10.1186/1742-2094-8-91[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFegsbfP&md5=3cdee6c1179c23c2d7b4976e41a416a4The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeysSwanson, Christine R.; Joers, Valerie; Bondarenko, Viktoriya; Brunner, Kevin; Simmons, Heather A.; Ziegler, Toni E.; Kemnitz, Joseph W.; Johnson, Jeffrey A.; Emborg, Marina E.Journal of Neuroinflammation (2011), 8 (), 91CODEN: JNOEB3; ISSN:1742-2094. (BioMed Central Ltd.)Background: Activation of the peroxisome proliferator-activated receptor gamma (PPAR-γ) has been proposed as a possible neuroprotective strategy to slow down the progression of early Parkinson's disease (PD). Here we report preclin. data on the use of the PPAR-γ agonist pioglitazone (Actos; Takeda Pharmaceuticals Ltd.) in a paradigm resembling early PD in nonhuman primates. Methods: Rhesus monkeys that were trained to perform a battery of behavioral tests received a single intracarotid arterial injection of 20 mL of saline contg. 3 mg of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Twenty-four hours later the monkeys were assessed using a clin. rating scale, matched accordingly to disability, randomly assigned to one of three groups [placebo (n = 5), 2.5 (n = 6) or 5 (n = 5) mg/kg of pioglitazone] and their treatments started. Three months after daily oral dosing, the animals were necropsied. Results: We obsd. significant improvements in clin. rating score (P = 0.02) in the animals treated with 5 mg/kg compared to placebo. Behavioral recovery was assocd. with preservation of nigrostriatal dopaminergic markers, obsd. as higher tyrosine hydroxylase (TH) putaminal optical d. (P = 0.011), higher stereol. cell counts of TH-ir (P = 0.02) and vesicular monoamine transporter-2 (VMAT-2)-ir nigral neurons (P = 0.006). Stereol. cell counts of Nissl-stained nigral neurons confirmed neuroprotection (P = 0.017). Pioglitazone-treated monkeys also showed a dose-dependent modulation of CD68-ir inflammatory cells, that was significantly decreased for 5 mg/kg treated animals compared to placebo (P = 0.018). A sep. expt. to assess CSF penetration of pioglitazone revealed that 5 mg/kg p.o. induced consistently higher levels than 2.5 mg/kg and 7.5 mg/kg. p.o. Conclusions: Our results indicate that oral administration of pioglitazone is neuroprotective when administered early after inducing a parkinsonian syndrome in rhesus monkeys and supports the concept that PPAR-γ is a viable target against neurodegeneration.
- 65Pinto, M.; Nissanka, N.; Peralta, S.; Brambilla, R.; Diaz, F.; Moraes, C. T. Pioglitazone Ameliorates the Phenotype of a Novel Parkinson’s Disease Mouse Model by Reducing Neuroinflammation. Mol. Neurodegener. 2016, 11, 25, DOI: 10.1186/s13024-016-0090-7[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjtVOqt7w%253D&md5=ef35f48cf4aff1882580062baf8227e2Pioglitazone ameliorates the phenotype of a novel Parkinson's disease mouse model by reducing neuroinflammationPinto, Milena; Nissanka, Nadee; Peralta, Susana; Brambilla, Roberta; Diaz, Francisca; Moraes, Carlos T.Molecular Neurodegeneration (2016), 11 (), 25/1-25/15CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The cause of the motor symptoms is the loss of dopaminergic neurons in the substantia nigra with consequent depletion of dopamine in the striatum. Although the etiol. of PD is unknown, mitochondrial dysfunctions, including cytochrome c oxidase (Complex IV) impairment in dopaminergic neurons, have been assocd. with the disease's pathophysiol. In order to analyze the role of Complex IV in PD, we knocked out Cox10 (essential for the maturation of COXI, a catalytic subunit of Complex IV) in dopaminergic neurons. We also tested whether the resulting phenotype was improved by stimulating the PPAR-γ pathway. Results:Cox10/DAT-cre mice showed decreased nos. of TH+ and DAT+ cells in the substantia nigra, early striatal dopamine depletion, motor defects reversible with L-DOPA treatment and hypersensitivity to L-DOPA with hyperkinetic behavior. We found that chronic pioglitazone (PPAR-γ agonist) treatment ameliorated the motor phenotype in Cox10/DAT-cre mice. Although neither mitochondrial function nor the no. of dopaminergic neurons was improved, neuroinflammation in the midbrain and the striatum was decreased. Conclusions: By triggering a mitochondrial Complex IV defect in dopaminergic neurons, we created a new mouse model resembling the late stages of PD with massive degeneration of dopaminergic neurons and striatal dopamine depletion. The motor phenotypes were improved by Pioglitazone treatment, suggesting that targetable secondary pathways can influence the development of certain forms of PD.
- 66Lecca, D.; Nevin, D. K.; Mulas, G.; Casu, M. A.; Diana, A.; Rossi, D.; Sacchetti, G.; Carta, A. R. Neuroprotective and Anti-Inflammatory Properties of a Novel Non-Thiazolidinedione PPARγ Agonist in Vitro and in MPTP-Treated Mice. Neuroscience 2015, 302, 23– 35, DOI: 10.1016/j.neuroscience.2015.04.026[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXntlWmsLY%253D&md5=a575391f7368c514c35c14866f405e56Neuroprotective and anti-inflammatory properties of a novel non-thiazolidinedione PPARγ agonist in vitro and in MPTP-treated miceLecca, D.; Nevin, D. K.; Mulas, G.; Casu, M. A.; Diana, A.; Rossi, D.; Sacchetti, G.; Carta, A. R.Neuroscience (Amsterdam, Netherlands) (2015), 302 (), 23-35CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)Peroxisome proliferator-activated receptor (PPAR)γ is a potential pharmacol. target for disease-modification in Parkinson's disease (PD), mainly acting by modulating the neuroinflammatory response. However, currently available agonists thiazolidinediones (TZDs) present limitations due to safety concerns. We evaluated a novel thiobarbituric-like compd. MDG548, which acts as a functional PPARγ agonist displaying higher and selective binding affinity as compared to TZDs. Neuroprotection by MDG548 was tested in vitro and in a mouse MPTP model of PD, and neuroinflammation was investigated as a putative underlying mechanism. Viability assay on rat cortical neurons showed lack of cytotoxic effect in the dose-range of 100 nM-10 μM, which was therefore used for testing in vitro protection against H2O2 and MPP+ neurotoxicity. MDG548 dose-dependently increased cell viability of rat cortical neurons co-treated with H2O2 or pre-exposed to MDG548 prior to H2O2. Moreover, MDG548 induced neuroprotection in MPP+-treated PC12 cells. NF-kB activation was investigated to assess anti-inflammatory activity. MDG548 dose-dependently decreased NF-kB activation induced by LPS (100 ng/100 mL) in HEK-Blue-hTLR4 cells. Given the supposed cancer risk of other PPARγ agonists, Ames test for genotoxicity was performed in Salmonella typhimurium TA100 and TA98 strains, showing that MDG548 was not genotoxic. In vivo, BL/6J mice were treated with MPTP (20 mg/kg i.p. once/day for 4 days) in assocn. with saline or MDG548 (2, 5, 10 mg/kg i.p.). Stereol. counting showed that MDG548 prevented the MPTP-induced redn. in TH-pos. cells in the substantia nigra compacta (SNc) at all doses tested. Moreover, MDG548 reduced reactive microglia and iNOS induction in the SNc. MDG548, being a non-TZD compd. with high PPARγ affinity, void of genotoxicity, and with in vitro as well as in vivo neuroprotective properties, provides a promising alternative in the search for safer PPARγ agonists to be tested as potential disease-modifying drugs in PD.
- 67Lecca, D.; Janda, E.; Mulas, G.; Diana, A.; Martino, C.; Angius, F.; Spolitu, S.; Casu, M. A.; Simbula, G.; Boi, L.; Batetta, B.; Spiga, S.; Carta, A. R. Boosting Phagocytosis and Anti-Inflammatory Phenotype in Microglia Mediates Neuroprotection by PPARγ Agonist MDG548 in Parkinson’s Disease Models. Br. J. Pharmacol. 2018, 175 (16), 3298– 3314, DOI: 10.1111/bph.14214[Crossref], [PubMed], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlSlur3N&md5=0082c9b67fbc756ae2bf83ee2024a6a0Boosting phagocytosis and anti-inflammatory phenotype in microglia mediates neuroprotection by PPARγ agonist MDG548 in Parkinson's disease modelsLecca, Daniela; Janda, Elzbieta; Mulas, Giovanna; Diana, Andrea; Martino, Concetta; Angius, Fabrizio; Spolitu, Stefano; Casu, Maria Antonietta; Simbula, Gabriella; Boi, Laura; Batetta, Barbara; Spiga, Saturnino; Carta, Anna R.British Journal of Pharmacology (2018), 175 (16), 3298-3314CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)Background and Purpose : Microglial phenotype and phagocytic activity are deregulated in Parkinson's disease (PD). PPARγ agonists are neuroprotective in exptl. PD, but their role in regulating microglial phenotype and phagocytosis has been poorly investigated. We addressed it by using the PPARγ agonist MDG548. Exptl. Approach : Murine microglial cell line MMGT12 was stimulated with LPS and/or MDG548, and their effect on phagocytosis of fluorescent microspheres or necrotic neurons was investigated by flow cytometry. Cytokines and markers of microglia phenotype, such as mannose receptor C type 1; MRC1 ,Ym1, CD68 were measured by eLisa and fluorescent immunohistochem. Levels of Beclin-1, which plays a role in microglial phagocytosis, were measured by Western blotting. In the in vivo MPTP-probenecid (MPTPp) model of PD in mice, MDG548 was tested on motor impairment, nigral neurodegeneration, microglial activation and phenotype. Chronic MPTPp treatment in mice down-regulated MRC1 and TGF-β and up-regulated TNF-α and IL-1β immunoreactivity in activated CD11b-pos. microglia, causing the death of nigral dopaminergic neurons. MDG548 arrested MPTPp-induced cell death, enhanced MRC1 and restored cytokine levels. Conclusions and Implications : This study adds a novel mechanism for PPARγ-mediated neuroprotection in PD and suggests that increasing phagocytic activity and anti-inflammatory markers may represent an effective disease-modifying approach.
- 68Swanson, C. R.; Du, E.; Johnson, D. A.; Johnson, J. A.; Emborg, M. E. Neuroprotective Properties of a Novel Non-Thiazoledinedione Partial PPAR-γ Agonist against MPTP. PPAR Res. 2013, 2013, 582809 DOI: 10.1155/2013/582809[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c7mtVamtA%253D%253D&md5=a426792c4fac2dc9f5595a986bb7f0f7Neuroprotective Properties of a Novel Non-Thiazoledinedione Partial PPAR- γ Agonist against MPTPSwanson Christine R; Du Eric; Johnson Delinda A; Johnson Jeffrey A; Emborg Marina EPPAR research (2013), 2013 (), 582809 ISSN:1687-4757.Activation of the peroxisome proliferator activated receptor-gamma (PPAR)- γ is proposed as a neuroprotective strategy to treat neurodegenerative disorders. In this study, we examined if LSN862 (LSN), a novel non-thiazoledinedione partial PPAR- γ agonist, was neuroprotective in a mouse model of Parkinson's disease (PD) and assessed possible mechanisms of action. LSN (3, 10, or 30 mg/kg) or vehicle was orally administered daily to C57BL/6 and antioxidant response element-human placental alkaline phosphatase (ARE-hPAP) reporter mice 3 days prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg, i.p. × 5 days) or PBS administration. LSN elicited a dose-dependent preservation of dopaminergic nigrostriatal innervation that was not associated with inhibition of MPTP metabolism or activation of Nrf2-ARE, although changes in NQO1 and SOD2 mRNA were observed. A significant dose-dependent downregulation in MAC-1 and GFAP positive cells was observed in MPTP + LSN-treated mice as well as significant downregulation of mRNA expression levels of these inflammatory markers. MPTP-induced increases in PPAR- γ and PGC1 α expression were ameliorated by LSN dosing. Our results demonstrate that oral administration of LSN is neuroprotective against MPTP-induced neurodegeneration, and this effect is associated with downregulation of neuroinflammation, decreased oxidative stress, and modulation of PPAR- γ and PGC1 α expression. These results suggest that LSN can be a candidate alternative non-thiazoledinedione partial PPAR- γ agonist for neuroprotective treatment of PD.
- 69Das, N. R.; Gangwal, R. P.; Damre, M. V.; Sangamwar, A. T.; Sharma, S. S. A PPAR-β/δ Agonist Is Neuroprotective and Decreases Cognitive Impairment in a Rodent Model of Parkinson’s Disease. Curr. Neurovasc. Res. 2014, 11 (2), 114– 124, DOI: 10.2174/1567202611666140318114037[Crossref], [PubMed], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXos1Ghurs%253D&md5=193337c81e37443c0771b819764cb85cA PPAR-β/δ Agonist is Neuroprotective and Decreases Cognitive Impairment in a Rodent Model of Parkinsonμs DiseaseDas, Nihar R.; Gangwal, Rahul P.; Damre, Mangesh V.; Sangamwar, Abhay T.; Sharma, Shyam S.Current Neurovascular Research (2014), 11 (2), 114-124CODEN: CNRUAM; ISSN:1875-5739. (Bentham Science Publishers Ltd.)Parkinson's disease (PD) is assocd. with higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of GW0742, a PPAR-β/δ agonist in rat model of cognitive impairment assocd. with PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) (100 μg/1 μl/side) produced significant cognitive dysfunctions. PPAR-β/δ agonist GW0742 at a dose of 30 and 100 μg/kg showed significant improvement in cognitive impairments caused by MPTP in rat model of PD as evident from passive avoidance and Morris water maze test. MPTP-induced massive oxidative damage and DNA fragmentation was ameliorated by GW0742 treatment as obsd. after MDA and GSH estn. and TUNEL assay. Tyrosine hydroxylase pos. neurons were decreased by 25% of normal control in MPTP group and GW0742 treatment restored tyrosine hydroxylase levels showing neuroprotective nature. Further, we performed physiol. based pharmacokinetic (PBPK) modeling study using GastroPlus to characterize the kinetics of GW0742 in the brain. The predicted amts. of GW0742 in brain suggest that it has the ability to cross the blood brain barrier. This study implicates the involvement of PPAR-β/δ in PD induced cognitive impairment.
- 70Uppalapati, D.; Das, N. R.; Gangwal, R. P.; Damre, M. V.; Sangamwar, A. T.; Sharma, S. S. Neuroprotective Potential of Peroxisome Proliferator Activated Receptor-α Agonist in Cognitive Impairment in Parkinson’s Disease: Behavioral, Biochemical, and PBPK Profile. PPAR Res. 2014, 2014, 753587, DOI: 10.1155/2014/753587[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crpvVKhtQ%253D%253D&md5=bf33ee81cecd6f594784b09d52e459e2Neuroprotective Potential of Peroxisome Proliferator Activated Receptor- α Agonist in Cognitive Impairment in Parkinson's Disease: Behavioral, Biochemical, and PBPK ProfileUppalapati Dedeepya; Das Nihar R; Sharma Shyam S; Gangwal Rahul P; Damre Mangesh V; Sangamwar Abhay TPPAR research (2014), 2014 (), 753587 ISSN:1687-4757.Parkinson's disease (PD) is a common neurodegenerative disorder affecting 1% of the population by the age of 65 years and 4-5% of the population by the age of 85 years. PD affects functional capabilities of the patient by producing motor symptoms and nonmotor symptoms. Apart from this, it is also associated with a higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of fenofibrate, a PPAR- α agonist in cognitive impairment model in PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (100 μg/1 μL/side) produced significant cognitive dysfunctions. Fenofibrate treatment at 10, 30, and 100 mg/kg for twenty-five days was found to be neuroprotective and improved cognitive impairment in MPTP-induced PD model as evident from behavioral, biochemical (MDA, GSH, TNF- α , and IL-6), immunohistochemistry (TH), and DNA fragmentation (TUNEL positive cells) studies. Further, physiologically based pharmacokinetic (PBPK) modeling study was performed using GastroPlus to characterize the kinetics of fenofibric acid in the brain. A good agreement was found between pharmacokinetic parameters obtained from the actual and simulated plasma concentration-time profiles of fenofibric acid. Results of this study suggest that PPAR- α agonist (fenofibrate) is neuroprotective in PD-induced cognitive impairment.
- 71Barbiero, J. K.; Santiago, R.; Tonin, F. S.; Boschen, S.; Da Silva, L. M.; De Paula Werner, M. F.; Da Cunha, C.; Lima, M. M. S.; Vital, M. A. B. F. PPAR-α Agonist Fenofibrate Protects against the Damaging Effects of MPTP in a Rat Model of Parkinson’s Disease. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2014, 53, 35– 44, DOI: 10.1016/j.pnpbp.2014.02.009[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpvFSrtb4%253D&md5=38fef16150ee1a1256328d105b6b2d21PPAR-α agonist fenofibrate protects against the damaging effects of MPTP in a rat model of Parkinson's diseaseBarbiero, Janaina K.; Santiago, Ronise; Tonin, Fernanda S.; Boschen, Suelen; da Silva, Luisa Mota; de Paula Werner, Maria Fernanda; da Cunha, Claudio; Lima, Marcelo M. S.; Vital, Maria A. B. F.Progress in Neuro-Psychopharmacology & Biological Psychiatry (2014), 53 (), 35-44CODEN: PNPPD7; ISSN:0278-5846. (Elsevier Inc.)Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The etiol. and pathogenesis of PD are still unknown, however, many evidences suggest a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction. The peroxisome proliferator-activated receptor (PPAR) ligands, a member of the nuclear receptor family, have anti-inflammatory activity over a variety of rodent's models for acute and chronic inflammation. PPAR-α agonists, a subtype of the PPAR receptors, such as fenofibrate, have been shown a major role in the regulation of inflammatory processes. Animal models of PD have shown that neuroinflammation is one of the most important mechanisms involved in dopaminergic cell death. In addn., anti-inflammatory drugs are able to attenuate toxin-induced parkinsonism. In this study we evaluated the effects of oral administration of fenofibrate 100 mg/kg 1 h after infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the SNpc. First, we assessed the motor behavior in the open field for 24 h, 7, 14 and 21 days after MPTP. Twenty-two days after surgery, the animals were tested for two-way active avoidance and forced swimming for evaluation regarding cognitive and depressive parameters, resp. Twenty-three days after infusion of the toxin, we quantified DA and turnover and evaluated oxidative stress through the measurement of GSH (glutathione peroxidase), SOD (superoxide dismutase) and LOOH (hydroperoxide lipid). The data show that fenofibrate was able to decrease hypolocomotion caused by MPTP 24 h after injury, depressive-like behavior 22 days after the toxin infusion, and also protected against decreased level of DA and excessive prodn. of reactive oxygen species (ROS) 23 days after surgery. Thus, fenofibrate has shown a neuroprotective effect in the MPTP model of Parkinson's disease.
- 72Martin, H. L.; Mounsey, R. B.; Sathe, K.; Mustafa, S.; Nelson, M. C.; Evans, R. M.; Teismann, P. A Peroxisome Proliferator-Activated Receptor-δ Agonist Provides Neuroprotection in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson’s Disease. Neuroscience 2013, 240, 191– 203, DOI: 10.1016/j.neuroscience.2013.02.058[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmsVGhs7s%253D&md5=f386ef071f15887b3027029ed80f9064A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's diseaseMartin, H. L.; Mounsey, R. B.; Sathe, K.; Mustafa, S.; Nelson, M. C.; Evans, R. M.; Teismann, P.Neuroscience (Amsterdam, Netherlands) (2013), 240 (), 191-203CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)Peroxisome proliferator-activated receptor (PPAR)-γ and PPARα have shown neuroprotective effects in models of Parkinson's disease (PD). The role of the third, more ubiquitous isoform PPARδ has not been fully explored. This study investigated the role of PPARδ in PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model the dopaminergic neurodegeneration of PD. In vitro administration of the PPARδ antagonist GSK0660 (1 μM) increased the detrimental effect of 1-methyl-4-phenylpyridinium iodide (MPP+) on cell viability, which was reversed by co-treatment with agonist GW0742 (1 μM). GW0742 alone did not affect MPP+ toxicity. PPARδ was expressed in the nucleus of dopaminergic neurons and in astrocytes. Striatal PPARδ levels were increased (over two-fold) immediately after MPTP treatment (30 mg/kg for 5 consecutive days) compared to saline-treated mice. PPARδ heterozygous mice were not protected against MPTP toxicity. Intra-striatal infusion of GW0742 (84 μg/day) reduced the MPTP-induced loss of dopaminergic neurons (5036 ± 195) when compared to vehicle-infused mice (3953 ± 460). These results indicate that agonism of PPARδ provides protection against MPTP toxicity, in agreement with the effects of other PPAR agonists.
- 73Lee, Y.; Cho, J.-H.; Lee, S.; Lee, W.; Chang, S.-C.; Chung, H. Y.; Moon, H. R.; Lee, J. Neuroprotective Effects of MHY908, a PPAR α/γ Dual Agonist, in a MPTP-Induced Parkinson’s Disease Model. Brain Res. 2019, 1704, 47– 58, DOI: 10.1016/j.brainres.2018.09.036[Crossref], [PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVGjur%252FE&md5=f81c90f7af067f46495c90315e3f22daNeuroprotective effects of MHY908, a PPAR a/g dual agonist, in a MPTP-induced Parkinson's disease modelLee, Yujeong; Cho, Jung-Hyun; Lee, Seulah; Lee, Wonjong; Chang, Seung-Cheol; Chung, Hae Young; Moon, Hyung Ryong; Lee, JaewonBrain Research (2019), 1704 (), 47-58CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)Here, we evaluated the neuroprotective effects of MHY908 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Pretreatment with MHY908 attenuated MPTP-induced dopaminergic neuronal loss and motor deficit. MPTP-induced glial activations were mitigated by MHY908 in the nigrostriatal pathway, and MHY908 effectively blocked 1-methyl-4-phenylpyridinium (MPP+)-induced cell death and ROS prodn. in SH-SY5Y neuroblastoma cells. Further study revealed MHY908 inhibited MPP+-induced astroglial activation by suppressing NF-kB signaling in primary astrocytes. Taken together, the present study suggests that PPAR a/dual agonists be considered potentially useful preventions for PD and other neurodegenerative diseases assocd. with neuroinflammation.
- 74Chen, L.; Xue, L.; Zheng, J.; Tian, X.; Zhang, Y.; Tong, Q. PPARß/δ Agonist Alleviates NLRP3 Inflammasome-Mediated Neuroinflammation in the MPTP Mouse Model of Parkinson’s Disease. Behav. Brain Res. 2019, 356, 483– 489, DOI: 10.1016/j.bbr.2018.06.005[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1agsb7I&md5=3c8e84371c2968069bfda5ade2238d17Pparss/δ agonist alleviates nlrp3 inflammasome-mediated neuroinflammation in the mptp mouse model of parkinson's diseaseChen, Linfang; Xue, Liujun; Zheng, Jinlong; Tian, Xiangyang; Zhang, Yingdong; Tong, QiangBehavioural Brain Research (2019), 356 (), 483-489CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)Recent studies have indicated that peroxisome proliferator-activated receptor β/δ (PPARss/δ) agonists exert neuroprotective effects in the model of Parkinson's disease (PD). Furthermore, PPARss/δ agonists have been shown to have potential anti-inflammatory activity, but the underlying mechanisms remain obscure. Emerging evidence indicates that the nucleotide-binding domain and leucine-rich-repeat-protein 3 (NLRP3) inflammasome-mediated neuroinflammation plays a crucial role in the pathogenesis of PD. In the present study we investigate whether PPARss/δ agonists alleviate NLRP3-mediated neuroinflammation in the 1- methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model of PD. We administered GW501516, a selective and high-affinity PPARss/δ agonist, via intracerebroventricular infusion. Locomotor activities were tested by open field tests and the pole test. The levels of dopamine and its metabolites were detd. using highperformance liq. chromatog. Dopaminergic neurodegeneration was assessed via Western blot anal. The levels of oxidative stress were detected via spectrophotometric assays. The expressions of pro-inflammatory cytokines were measured by performing quant. real-time RT-PCR and ELISA. Western blot anal. was used to assess NLRP3 inflammasome activation. Our results show that GW501516 reduced movement impairment in PD mice; furthermore, it attenuated dopaminergic neurodegeneration in the midbrain and the depletion of dopamine in the striatum and it inhibited inflammatory reactions and NLRP3 inflammasome activation in the midbrain of PD mice. More importantly, it attenuated astrocytic reaction but had no significant effect on microglial reaction in the midbrain of PD mice. Collectively, our findings demonstrate for the first time that the specific PPARss/δ agonist GW501516 alleviates NLRP3 inflammasome-mediated neuroinflammation in astrocytes in the MPTP mouse model of PD.
- 75Mounsey, R. B.; Martin, H. L.; Nelson, M. C.; Evans, R. M.; Teismann, P. The Effect of Neuronal Conditional Knock-out of Peroxisome Proliferator-Activated Receptors in the MPTP Mouse Model of Parkinson’s Disease. Neuroscience 2015, 300, 576– 584, DOI: 10.1016/j.neuroscience.2015.05.048[Crossref], [PubMed], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpsVymt7w%253D&md5=b88a0c77bcb54c7c09030ac571547439The effect of neuronal conditional knock-out of peroxisome proliferator-activated receptors in the MPTP mouse model of Parkinson's diseaseMounsey, R. B.; Martin, H. L.; Nelson, M. C.; Evans, R. M.; Teismann, P.Neuroscience (Amsterdam, Netherlands) (2015), 300 (), 576-584CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)Activation of peroxisome proliferator-activated receptors (PPARs), namely PPARγ and PPARδ, has been shown to provide neuroprotection in a no. of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease (PD). The obsd. neuroprotective effects in exptl. models of PD have been linked to anti-oxidant and anti-inflammatory actions. This study aimed to analyze the full influence of these receptors in neuroprotection by generating a nerve cell-specific conditional knock-out of these receptors and subjecting these genetically modified mice to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to model dopaminergic degeneration. Mice null for both receptors show the lowest levels of tyrosine hydroxylase (TH)-pos. cell bodies following MPTP administration. Presence of one or both these receptors show a trend toward protection against this degeneration, as higher dopaminergic cell immunoreactivity and striatal monoamine levels are evident. These data supplement recent studies that have elected to use agonists of the receptors to regulate immune responses. The results place further importance on the activation of PPARs and the neuroprotective roles these have in inflammatory processes linked to neurodegenerative processes.
- 76Tong, Q.; Wu, L.; Gao, Q.; Ou, Z.; Zhu, D.; Zhang, Y. PPARβ/δ Agonist Provides Neuroprotection by Suppression of IRE1α–Caspase-12-Mediated Endoplasmic Reticulum Stress Pathway in the Rotenone Rat Model of Parkinson’s Disease. Mol. Neurobiol. 2016, 53 (8), 3822– 3831, DOI: 10.1007/s12035-015-9309-9[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFKhu73F&md5=e3b59fa369bf8392cf8c7c8183f91d60PPARβ/δ Agonist Provides Neuroprotection by Suppression of IRE1α-Caspase-12-Mediated Endoplasmic Reticulum Stress Pathway in the Rotenone Rat Model of Parkinson's DiseaseTong, Qiang; Wu, Liang; Gao, Qing; Ou, Zhou; Zhu, Dongya; Zhang, YingdongMolecular Neurobiology (2016), 53 (6), 3822-3831CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Two recent studies demonstrated that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) agonists exerted neuroprotective effects in mouse model of Parkinson's disease (PD). However, the underlying mechanisms remain unknown. Endoplasmic reticulum (ER) stress plays a major role in rotenone-induced dopaminergic neuronal degeneration. In the present study, we explored whether GW501516, a selective and high-affinity PPARβ/δ agonist, could protect the dopaminergic neurons against degeneration and improve PD behavior via suppressing the ER stress in the rotenone rat model of PD. GW501516 was administered intracerebroventricular infusion. Catalepsy and open field tests were used to test catalepsy and locomotor activities. The levels of dopamine and its metabolites were detd. using high-performance liq. chromatog. Western blot and immunohistochem. anal. were performed to assess dopaminergic neuronal degeneration. Quant. real-time RT-PCR and Western blot anal. were executed to detect ER stress. TUNEL and immunohistochem. assays were used to detect ER stress-mediated apoptosis. Our results showed that GW501516 ameliorated the catalepsy symptom and increased locomotor activity. Meanwhile, GW501516 partially reversed the loss of dopaminergic neurons. Moreover, GW501516 suppressed the activation of ER stress markers including inositol-requiring enzyme 1α (IRE1α) and caspase-12. Furthermore, GW501516 inhibited caspase-12-mediated neuronal apoptosis. These findings suggest that GW501516 conferred neuroprotection of not only biochem. and pathol. attenuation but also behavioral improvement in the rotenone rat model of PD. More importantly, we demonstrated for the first time that suppressing IRE1α-caspase-12-mediated ER stress pathway may represent one potential mechanism underlying the neuroprotective effects of PPARβ/δ agonist in the rotenone rat model of PD.
- 77Bonato, J. M.; Bassani, T. B.; Milani, H.; Vital, M. A. B. F.; de Oliveira, R. M. W. Pioglitazone Reduces Mortality, Prevents Depressive-like Behavior, and Impacts Hippocampal Neurogenesis in the 6-OHDA Model of Parkinson’s Disease in Rats. Exp. Neurol. 2018, 300, 188– 200, DOI: 10.1016/j.expneurol.2017.11.009[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFaqu7%252FJ&md5=b0e6773d9e5aec41f39ffb95e03385faPioglitazone reduces mortality, prevents depressive-like behavior, and impacts hippocampal neurogenesis in the 6-OHDA model of Parkinson's disease in ratsBonato, Jessica Mendes; Bassani, Taysa Bervian; Milani, Humberto; Vital, Maria Aparecida Barbato Frazao; de Oliveira, Rubia Maria WeffortExperimental Neurology (2018), 300 (), 188-200CODEN: EXNEAC; ISSN:0014-4886. (Elsevier Inc.)Deficiencies in adult hippocampal neurogenesis have been suggested to be a possible pathophysiol. mechanism that underlies depressive symptoms that are often obsd. in patients with Parkinson's disease (PD). Pioglitazone, a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, has been shown to exert antiinflammatory and antidepressant effects and modulate neural plasticity in several neurodegenerative disorders. The present study investigated the effects of pioglitazone on depressive phenotypes and adult hippocampal neurogenesis in a rat model of PD that was induced by bilateral 6-hydroxydopamine (6-OHDA) infusions in the substantia nigra pars compact (SNpc). Rats with SNpc and ventral tegmental area (VTA) neurodegeneration exhibited despair-like behavior, concomitant with persistent microglial activation in the hippocampus. Pioglitazone reduced the rate of mortality and attenuated microglial activation in the early phase of 6-OHDA-induced nigral lesions. Pioglitazone exerted antidepressant-like effects and increased the survival of neurons in the hippocampus in rats with nigral lesions. These results indicate that pioglitazone exerts neuroprotective effects by facilitating hippocampal neurogenesis in 6-OHDA-lesioned rats, which might contribute to its antidepressant-like effect.
- 78Machado, M. M. F.; Bassani, T. B.; Cóppola-Segovia, V.; Moura, E. L. R.; Zanata, S. M.; Andreatini, R.; Vital, M. A. B. F. PPAR-γ Agonist Pioglitazone Reduces Microglial Proliferation and NF-KB Activation in the Substantia Nigra in the 6-Hydroxydopamine Model of Parkinson’s Disease. Pharmacol. Rep. 2019, 71 (4), 556– 564, DOI: 10.1016/j.pharep.2018.11.005[Crossref], [PubMed], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVegu7zJ&md5=393a932f3b2e0814357c21c4153d7c02PPAR-γ agonist pioglitazone reduces microglial proliferation and NF-κB activation in the substantia nigra in the 6-hydroxydopamine model of Parkinson's diseaseMachado, Meira Maria Forcelini; Bassani, Taysa Bervian; Coppola-Segovia, Valentin; Moura, Eric Luiz Rossa; Zanata, Silvio Marques; Andreatini, Roberto; Vital, Maria Aparecida Barbato FrazaoPharmacological Reports (2019), 71 (4), 556-564CODEN: PRHEDU; ISSN:2299-5684. (Elsevier B.V.)Peroxisome proliferator-activated receptor γ (PPAR-γ) agonists have received much attention in research because of their neuroprotective and anti-inflammatory effects that reduce cell death and halt the progression of neurodegeneration. Thus, this study obsd. the pioglitazone effects on the main inflammatory markers after 6-hydroxydopamine (6-OHDA) lesion. The effects of a 5-day administration of the PPAR-γ agonist pioglitazone (30 mg/kg) in male Wistar rats that received bilateral intranigral infusions of 6-OHDA. After surgery, the rats were evaluated in the open-field test on days 1,7,14, and 21. Immediately after the behavioral tests on day 21, the rats were euthanized, and the substantia nigra was removed to analyze the expression of nuclear factor κB (NF-κB) and IκB by western blot. To immunohistochem., animals were intracardially perfused, with brain removal that was frozen and sectioned, being selected slices of the SNc region to detect tyrosine hydroxylase (TH) immunoreactivity, microglia activation (Iba-1) and NF-κB translocation in the nucleus. Pioglitazone protected rats against hypolocomotion and 6-OHDA-induced dopaminergic neurodegeneration on day 7. Decreases in the microglial activation and the NF-κB expression were obsd., and the p65 activation was inhibited. These results suggest that pioglitazone may be a potential adjuvant for the treatment of Parkinson's disease because of its effects on pathol. markers of the progression of neurodegeneration.
- 79Lee, E. Y.; Lee, J. E.; Park, J. H.; Shin, I. C.; Koh, H. C. Rosiglitazone, a PPAR-γ Agonist, Protects against Striatal Dopaminergic Neurodegeneration Induced by 6-OHDA Lesions in the Substantia Nigra of Rats. Toxicol. Lett. 2012, 213 (3), 332– 344, DOI: 10.1016/j.toxlet.2012.07.016[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlSnsL%252FE&md5=add46159419011ab9bef26dc89de04adRosiglitazone, a PPAR-γ agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of ratsLee, Eun Young; Lee, Jeong Eun; Park, Jae Hyeon; Shin, In Chul; Koh, Hyun ChulToxicology Letters (2012), 213 (3), 332-344CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Rosiglitazone is a commonly prescribed insulin-sensitizing drug with selective agonistic activity at the peroxisome proliferator-activated receptor-γ (PPARγ). Previously, rosiglitazone was shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), an effect attributed to its anti-inflammatory properties. To elucidate the neuroprotective mechanisms of rosiglitazone, we investigated the effects of rosiglitazone on the expressions of striatal tyrosine hydroxylase (TH), cyclooxygenase-2 (COX-2) and glial fibrillary acidic protein (GFAP) in a 6-OHDA-lesioned rat PD model. Rosiglitazone (3 mg/kg) was administered i.p. at 24 h and 30 min prior to the creation of an intranigral 6-OHDA lesion. A redn. in TH protein expression began at 3 days and a prominent decrease was obsd. at 7 days post-lesion, and decreases of dopamine (DA) levels began at 1 day post-lesion. In contrast, GFAP expression was significantly increased at 3 days and preserved for up to 7 days post-lesion and the patterns of GFAP expression was inversely correlated to changes in TH expression. Furthermore, COX-2 expression in the rostral striatum showed a significant increase at 6 h post-lesion while that of the caudal striatum was increased at 12 h. In the 6-OHDA-lesioned model, the activation of PPARγ by rosiglitazone significantly prevented TH protein expression redns., and inhibited 6-OHDA-induced microglia activation in striatum. In addn., rosiglitazone attenuated in prodn. of both COX-2 and TNF-α expression. In contrast, rosiglitazone pretreatment led to greater increases in striatal GFAP expression than 6-OHDA alone and changes in the expression of this protein preceded the changes that were seen with TH expression. These results suggest that the neuroprotection obsd. with rosiglitazone treatment may be partially due to the attenuation of COX-2 prodn. and the strengthening of astrocyte function. These results provide insight into the neuroprotective mechanisms of rosiglitazone against 6-OHDA-induced neuronal damages.
- 80Martinez, A. A.; Morgese, M. G.; Pisanu, A.; Macheda, T.; Paquette, M. A.; Seillier, A.; Cassano, T.; Carta, A. R.; Giuffrida, A. Activation of PPAR Gamma Receptors Reduces Levodopa-Induced Dyskinesias in 6-OHDA-Lesioned Rats. Neurobiol. Dis. 2015, 74, 295– 304, DOI: 10.1016/j.nbd.2014.11.024[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitV2msL%252FF&md5=c91b97782ba953b7623a89c77b0493d6Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned ratsMartinez, A. A.; Morgese, M. G.; Pisanu, A.; Macheda, T.; Paquette, M. A.; Seillier, A.; Cassano, T.; Carta, A. R.; Giuffrida, A.Neurobiology of Disease (2015), 74 (), 295-304CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)Long-term administration of L-3,4-dihydroxyphenylalanine (levodopa), the mainstay treatment for Parkinson's disease (PD), is accompanied by fluctuations in its duration of action and motor complications (dyskinesia) that dramatically affect the quality of life of patients. Levodopa-induced dyskinesias (LID) can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of levodopa, which causes increasingly severe axial, limb, and orofacial abnormal involuntary movements (AIMs) over time. In previous studies, we showed that the direct activation of CB1 cannabinoid receptors alleviated rat AIMs. Interestingly, elevation of the endocannabinoid anandamide by URB597 (URB), an inhibitor of endocannabinoid catabolism, produced an anti-dyskinetic response that was only partially mediated via CB1 receptors and required the concomitant blockade of transient receptor potential vanilloid type-1 (TRPV1) channels by capsazepine (CPZ) (Morgese et al., 2007). In this study, we showed that the stimulation of peroxisome proliferator-activated receptors (PPAR), a family of transcription factors activated by anandamide, contributes to the anti-dyskinetic effects of URB + CPZ, and that the direct activation of the PPARγ subtype by rosiglitazone (RGZ) alleviates levodopa-induced AIMs in 6-OHDA rats. AIM redn. was assocd. with an attenuation of levodopa-induced increase of dynorphin, zif-268, and of ERK phosphorylation in the denervated striatum. RGZ treatment did not decrease striatal levodopa and dopamine bioavailability, nor did it affect levodopa anti-parkinsonian activity. Collectively, these data indicate that PPARγ may represent a new pharmacol. target for the treatment of LID.
- 81Gottschalk, C. G.; Roy, A.; Jana, M.; Kundu, M.; Pahan, K. Activation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic Neurons. Mol. Neurobiol. 2019, 56 (11), 7872– 7887, DOI: 10.1007/s12035-019-01649-y[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVCitLrO&md5=1e18d8ef00f254fdefa0e10784ffa4faActivation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic NeuronsGottschalk, Carl G.; Roy, Avik; Jana, Malabendu; Kundu, Madhuchhanda; Pahan, KalipadaMolecular Neurobiology (2019), 56 (11), 7872-7887CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Nuclear receptor related 1 protein (Nurr1) is an important transcription factor required for differentiation and maintenance of midbrain dopaminergic (DA) neurons. Since decrease in Nurr1 function either due to diminished expression or rare mutation is assocd. with Parkinson's disease (PD), upregulation of Nurr1 may be beneficial for PD. However, such mechanisms are poorly understood. This study underlines the importance of peroxisome proliferator-activated receptor (PPAR)α in controlling the transcription of Nurr1. Our mRNA analyses followed by different immunoassays clearly indicated that PPARα agonist gemfibrozil strongly upregulated the expression of Nurr1 in wild-type, but not PPARα-/-, DA neurons. Moreover, identification of conserved PPRE in the promoter of Nurr1 gene followed by chromatin immunopptn. anal., PPRE luciferase assay, and manipulation of Nurr1 gene by viral transduction of different PPARα plasmids confirmed that PPARα was indeed involved in the expression of Nurr1. Finally, oral administration of gemfibrozil increased Nurr1 expression in vivo in nigra of wild-type, but not PPARα-/-, mice identifying PPARα as a novel regulator of Nurr1 expression and assocd. protection of DA neurons.
- 82Brauer, R.; Bhaskaran, K.; Chaturvedi, N.; Dexter, D. T.; Smeeth, L.; Douglas, I. Glitazone Treatment and Incidence of Parkinson’s Disease among People with Diabetes: A Retrospective Cohort Study. PLoS Med. 2015, 12 (7), e1001854, DOI: 10.1371/journal.pmed.1001854[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlsFOgu7k%253D&md5=b5a6318677eb4d902ccf391705669b5eGlitazone treatment and incidence of parkinson's disease among people with diabetes: a retrospective cohort studyBrauer, Ruth; Bhaskaran, Krishnan; Chaturvedi, Nishi; Dexter, David T.; Smeeth, Liam; Douglas, IanPLoS Medicine (2015), 12 (7), e1001854/1-e1001854/16CODEN: PMLEAC; ISSN:1549-1277. (Public Library of Science)Background Recent in vitro and animal expts. suggest that peroxisome proliferation-activated receptor gamma (PPARγ) agonist medications, such as antidiabetic glitazone (GTZ) drugs, are neuroprotective in models of Parkinson's disease (PD). These findings have not been tested in humans. We hypothesized that individuals prescribed GTZ drugs would have a lower incidence of PD compared to individuals prescribed other treatments for diabetes. Methods and Findings Using primary care data from the United Kingdom Clin. Practice Research Datalink (CPRD), we conducted a retrospective cohort study in which individuals with diabetes who were newly prescribed GTZ (GTZ-exposed group) were matched by age, sex, practice, and diabetes treatment stage with up to five individuals prescribed other diabetes treatments (other antidiabetic drug-exposed group). Patients were followed up from 1999 until the first recording of a PD diagnosis, end of observation in the database, or end of the study (1 August 2013). An incidence rate ratio (IRR) was calcd. using conditional Poisson regression, adjusted for possible confounders. 44,597 GTZ exposed individuals were matched to 120,373 other antidiabetic users. 175 GTZ-exposed individuals were diagnosed with PD compared to 517 individuals in the other antidiabetic drug-exposed group. The incidence rate (IR) of PD in the GTZ-exposed group was 6.4 per 10,000 patient years compared with 8.8 per 10,000 patient years in those prescribed other antidiabetic treatments (IRR 0.72, 95% confidence interval [CI] 0.60-0.87). Adjustments for potential confounding variables, including smoking, other medications, head injury, and disease severity, had no material impact (fully adjusted IRR 0.75, 0.59-0.94). The risk was reduced in those with current GTZ prescriptions (current GTZ-exposed IRR 0.59, 0.46-0.77) but not reduced among those with past prescriptions (past GTZ-exposed IRR 0.85, 0.65-1.10). Our study only included patients with diabetes who did not have a PD diagnosis when they were first prescribed GTZ, and thus, it cannot establish whether GTZ use prevents or slows the progression of PD. Conclusions In patients with diabetes, a current prescription for GTZ is assocd. with a redn. in incidence of PD. This suggests PPAR gamma pathways may be a fruitful drug target in PD.
- 83Mutez, E.; Duhamel, A.; Defebvre, L.; Bordet, R.; Destée, A.; Kreisler, A. Lipid-Lowering Drugs Are Associated with Delayed Onset and Slower Course of Parkinson’s Disease. Pharmacol. Res. 2009, 60 (1), 41– 45, DOI: 10.1016/j.phrs.2009.03.010[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlslWlu7w%253D&md5=8b0c8dcff57b176f8b2a76a5981cf4cfLipid-lowering drugs are associated with delayed onset and slower course of Parkinson's diseaseMutez, Eugenie; Duhamel, Alain; Defebvre, Luc; Bordet, Regis; Destee, Alain; Kreisler, AlexandrePharmacological Research (2009), 60 (1), 41-45CODEN: PHMREP; ISSN:1043-6618. (Elsevier Ltd.)Fibrates and statins activate the Peroxisome Proliferator-Activated Receptor alpha (PPAR-alpha). This nuclear receptor regulates genes governing inflammation, apoptosis and oxidative stress, three important mechanisms of neuronal death in Parkinson's disease (PD). We retrospectively studied the effect of statins and fibrates in a cohort of 419 patients with PD. In PD patients receiving either a statin or a fibrate, the mean age of disease onset was delayed by nearly 9 years, when compared with (control) PD patients not taking a lipid-lowering treatment. According to a mixed linear model, the increase in the levodopa-equiv. daily dose over 2 years was significantly smaller in the group taking a statin (+24 mg) than in the matched control group (+212 mg) (p = 0.004), whereas the Unified Parkinson's Disease Rating Scale motor score progression was similar. The course of the disease in patients taking a fibrate did not differ from the controls. These data suggest that lipid-lowering drugs may have a disease modifier effect, with a stronger action for statins than for fibrates.
- 84Szalardy, L.; Zadori, D.; Tanczos, E.; Simu, M.; Bencsik, K.; Vecsei, L.; Klivenyi, P. Elevated Levels of PPAR-Gamma in the Cerebrospinal Fluid of Patients with Multiple Sclerosis. Neurosci. Lett. 2013, 554, 131– 134, DOI: 10.1016/j.neulet.2013.08.069[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslCls7zN&md5=ca0cdef78d24e6b93a0a4e15a312ae82Elevated levels of PPAR-gamma in the cerebrospinal fluid of patients with multiple sclerosisSzalardy, Levente; Zadori, Denes; Tanczos, Ervin; Simu, Mihaela; Bencsik, Krisztina; Vecsei, Laszlo; Klivenyi, PeterNeuroscience Letters (2013), 554 (), 131-134CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcriptional factor involved in the regulation of glucose and lipid metab., has gained interest as a potential therapeutic target in multiple sclerosis (MS) due to its potent immunoregulatory properties and the therapeutic efficacy of its ligands in exptl. autoimmune encephalitis (EAE). Elevated expression of PPARγ has been obsd. in the spinal cord of EAE mice and in an in vitro model of antigen-induced demyelination; however, no reports have yet been available on the PPARγ status in the central nervous system of human individuals with MS. Aiming to identify a possible alteration, the present study assessed the levels of PPARγ protein in the cerebrospinal fluid (CSF) of MS patients via ELISA technique. We report a pronounced elevation in the CSF levels of PPARγ in MS patients (n = 35) compared to non-inflammatory controls (n = 22). This elevation was independent of blood-CSF barrier integrity, but correlated with CSF white blood cell count and IgG index, assocg. the obsd. elevation with neuroinflammation. Controlling for potential confounders, the CSF levels of PPARγ further displayed a moderate but significant assocn. with clin. severity. Corroborating with prior exptl. findings, these results may contribute to our understanding about the role of PPARγ in MS, and may implicate this protein as a potential CSF biomarker of the disease.
- 85Szalardy, L.; Zadori, D.; Bencsik, K.; Vecsei, L.; Klivenyi, P. Unlike PPARgamma, Neither Other PPARs nor PGC-1alpha Is Elevated in the Cerebrospinal Fluid of Patients with Multiple Sclerosis. Neurosci. Lett. 2017, 651, 128– 133, DOI: 10.1016/j.neulet.2017.05.008[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXns1als7k%253D&md5=e145306ea529f1a35e307f9c794eea34Unlike PPARgamma, neither other PPARs nor PGC-1alpha is elevated in the cerebrospinal fluid of patients with multiple sclerosisSzalardy, Levente; Zadori, Denes; Bencsik, Krisztina; Vecsei, Laszlo; Klivenyi, PeterNeuroscience Letters (2017), 651 (), 128-133CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Corroborating with prior exptl. findings, we recently reported the pronounced elevation of peroxisome proliferator-activated receptor gamma (PPARγ) protein concn. in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS), in assocn. with neuroinflammatory markers and clin. severity. Based on subsequent reports on the possible involvement of other PPARs and PPARγ coactivator-1alpha (PGC-1α) in neuroinflammation in MS, we analyzed the protein levels of PPARα, PPARβ/δ, and PGC-1α in a subset of CSF samples from the same cohort of relapsing-remitting MS patients. Unlike PPARγ, none of these proteins were found elevated in MS patients (n = 25) compared to non-inflammatory controls (n = 16), with the levels of PPARα and PPARβ/δ found generally below the limit of detection, and that of PGC-1α being detectable but comparable in both groups. The clin. and lab. assocns. previously reported with PPARγ were however significant even in this smaller subset. The potential underlying causes of these differential alterations are discussed. The findings suggest that despite their proposed involvement in the regulation of inflammatory processes in MS, PPARα, PPARβ/δ, and PGC-1α proteins are not potential biomarkers of neuroinflammation in MS, and indicate a preferential role of PPARγ in the endogenous regulation of autoimmune response in the human CNS within its receptor family.
- 86Wouters, E.; Grajchen, E.; Jorissen, W.; Dierckx, T.; Wetzels, S.; Loix, M.; Tulleners, M. P.; Staels, B.; Stinissen, P.; Haidar, M.; Bogie, J. F. J.; Hendriks, J. J. A. Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis. Int. J. Mol. Sci. 2020, 21 (23), 9329, DOI: 10.3390/ijms21239329[Crossref], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXotVyitA%253D%253D&md5=3b492c9f1e5a0cc035226e3d12ff9e1dAltered PPARγ expression promotes myelin-induced foam cell formation in macrophages in multiple sclerosisWouters, Elien; Grajchen, Elien; Jorissen, Winde; Dierckx, Tess; Wetzels, Suzan; Loix, Melanie; Tulleners, Marie Paule; Staels, Bart; Stinissen, Piet; Haidar, Mansour; Bogie, Jeroen F. J.; Hendriks, Jerome J. A.International Journal of Molecular Sciences (2020), 21 (23), 9329CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)Macrophages play a crucial role during the pathogenesis of multiple sclerosis (MS), a neuroinflammatory autoimmune disorder of the central nervous system. Important regulators of the metabolic and inflammatory phenotype of macrophages are liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). Previously, it has been reported that PPARγ expression is decreased in peripheral blood mononuclear cells of MS patients. The goal of the present study was to det. to what extent PPARγ, as well as the closely related nuclear receptors PPARα and β and LXRα and β, are differentially expressed in monocytes from MS patients and how this change in expression affects the function of monocyte-derived macrophages. We demonstrate that monocytes of relapsing-remitting MS patients display a marked decrease in PPARγ expression, while the expression of PPARα and LXRα/β is not altered. Interestingly, exposure of monocyte-derived macrophages from healthy donors to MS-assocd. proinflammatory cytokines mimicked this redn. in PPARγ expression. While a reduced PPARγ expression did not affect the inflammatory and phagocytic properties of myelin-loaded macrophages, it did impact myelin processing by increasing the intracellular cholesterol load of myelin-phagocytosing macrophages. Collectively, our findings indicate that an inflammation-induced redn. in PPARγ expression promotes myelin-induced foam cell formation in macrophages in MS.
- 87Feinstein, D. L.; Galea, E.; Gavrilyuk, V.; Brosnan, C. F.; Whitacre, C. C.; Dumitrescu-Ozimek, L.; Landreth, G. E.; Pershadsingh, H. A.; Weinberg, G.; Heneka, M. T. Peroxisome Proliferator-Activated Receptor-γ Agonists Prevent Experimental Autoimmune Encephalomyelitis. Ann. Neurol. 2002, 51 (6), 694– 702, DOI: 10.1002/ana.10206[Crossref], [PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhsFygsb0%253D&md5=8c9aad931d21860ef88dd3d987d66dcdPeroxisome proliferator-activated receptor-γ agonists prevent experimental autoimmune encephalomyelitisFeinstein, Douglas L.; Galea, Elena; Gavrilyuk, Vitaliy; Brosnan, Celia F.; Whitacre, Caroline C.; Dumitrescu-Ozimek, Lucia; Landreth, Gary E.; Pershadsingh, Harrihar A.; Weinberg, Guy; Heneka, Michael T.Annals of Neurology (2002), 51 (6), 694-702CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)The development of clin. symptoms in multiple sclerosis and its animal model exptl. autoimmune encephalomyelitis (EAE) involves T-cell activation and migration into the central nervous system, prodn. of glial-derived inflammatory mols., and demyelination and axonal damage. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARγ ligand Pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clin. signs when it was provided after disease onset. Clin. symptoms were reduced by two other PPARγ agonists, suggesting a role for PPARγ activation in protective effects. The suppression of clin. signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen-dependent interferon-γ prodn. from EAE-derived T cells. These results suggest that orally administered PPARγ agonists could provide therapeutic benefit in demyelinating disease.
- 88Klotz, L.; Burgdorf, S.; Dani, I.; Saijo, K.; Flossdorf, J.; Hucke, S.; Alferink, J.; Novak, N.; Beyer, M.; Mayer, G.; Langhans, B.; Klockgether, T.; Waisman, A.; Eberl, G.; Schultze, J.; Famulok, M.; Kolanus, W.; Glass, C.; Kurts, C.; Knolle, P. The Nuclear Receptor PPARγ Selectively Inhibits Th17 Differentiation in a T Cell–Intrinsic Fashion and Suppresses CNS Autoimmunity. J. Exp. Med. 2009, 206 (10), 2079– 2089, DOI: 10.1084/jem.20082771[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1SrtbvE&md5=a0d5f5c62100d9c29abbc84d8f3f9216The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunityKlotz, Luisa; Burgdorf, Sven; Dani, Indra; Saijo, Kaoru; Flossdorf, Juliane; Hucke, Stephanie; Alferink, Judith; Novak, Nina; Beyer, Marc; Mayer, Gunter; Langhans, Birgit; Klockgether, Thomas; Waisman, Ari; Eberl, Gerard; Schultze, Joachim; Famulok, Michael; Kolanus, Waldemar; Glass, Christopher; Kurts, Christian; Knolle, Percy A.Journal of Experimental Medicine (2009), 206 (10), 2079-2089CODEN: JEMEAV; ISSN:0022-1007. (Rockefeller University Press)T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-β/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor-related orphan receptor γt (RORγt). We identify the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) as a key neg. regulator of human and mouse Th17 differentiation. PPARγ activation in CD4+ T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPARγ involved inhibition of TGF-β/IL-6-induced expression of RORγt in T cells. Pharmacol. activation of PPARγ prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the RORγt promoter in T cells, thus interfering with RORγt transcription. Both T cell-specific PPARγ knockout and endogenous ligand activation revealed the physiol. role of PPARγ for continuous T cell-intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4+ T cells from healthy controls and MS patients were strongly susceptible to PPARγ-mediated suppression of Th17 differentiation. In summary, we report a PPARγ-mediated T cell-intrinsic mol. mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacol. modulation. We therefore propose that PPARγ represents a promising mol. target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.
- 89Chedrawe, M. A. J.; Holman, S. P.; Lamport, A.-C.; Akay, T.; Robertson, G. S. Pioglitazone Is Superior to Quetiapine, Clozapine and Tamoxifen at Alleviating Experimental Autoimmune Encephalomyelitis in Mice. J. Neuroimmunol. 2018, 321, 72– 82, DOI: 10.1016/j.jneuroim.2018.06.001[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFSqsL7M&md5=a684196848748f42945705de45477401Pioglitazone is superior to quetiapine, clozapine and tamoxifen at alleviating experimental autoimmune encephalomyelitis in miceChedrawe, Matthew A. J.; Holman, Scott P.; Lamport, Anna-Claire; Akay, Turgay; Robertson, George S.Journal of Neuroimmunology (2018), 321 (), 72-82CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)Recent evidence suggests that clozapine and quetiapine (atypical antipsychotics), tamoxifen (selective-estrogen receptor modulator) and pioglitazone (PPARγ agonist) may improve functional recovery in multiple sclerosis (MS). We have compared the effectiveness of oral administration of these drugs, beginning at peak disease, at reducing ascending paralysis, motor deficits and demyelination in mice subjected to exptl. autoimmune encephalomyelitis (EAE). Mice were immunized with an immunogenic peptide corresponding to amino acids 35-55 of the myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant and injected with pertussis toxin to induce EAE. Unlike clozapine, quetiapine and tamoxifen, administration of pioglitazone beginning at peak disease decreased both clin. scores and lumbar white matter loss in EAE mice. Using kinematic gait anal., we found that pioglitazone also maintained normal movement of the hip, knee and ankle joints for at least 44 days after MOG35-55 immunization. This long-lasting preservation of hindleg joint movements was accompanied by reduced white matter loss, microglial and macrophage activation and the expression of pro-inflammatory genes in the lumbar spinal cords of EAE mice. These results support clin. findings that suggest pioglitazone may reduce the progressive loss of motor function in MS by decreasing inflammation and myelin damage.
- 90Diab, A.; Deng, C.; Smith, J. D.; Hussain, R. Z.; Phanavanh, B.; Lovett-Racke, A. E.; Drew, P. D.; Racke, M. K. Peroxisome Proliferator-Activated Receptor-γ Agonist 15-Deoxy-Δ12,1412,14-Prostaglandin J2 Ameliorates Experimental Autoimmune Encephalomyelitis. J. Immunol. 2002, 168 (5), 2508– 2515, DOI: 10.4049/jimmunol.168.5.2508[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhvVegsbk%253D&md5=73e71568a1466397765d5400221c5bd2Peroxisome proliferator-activated receptor-γ agonist 15-deoxy-Δ12,14-prostaglandin J2 ameliorates experimental autoimmune encephalomyelitisDiab, Asim; Deng, Caishu; Smith, Jeff D.; Hussain, Rehana Z.; Phanavanh, Bounleut; Lovett-Racke, Amy E.; Drew, Paul D.; Racke, Michael K.Journal of Immunology (2002), 168 (5), 2508-2515CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)Peroxisome proliferator-activated receptors (PPAR) are members of a nuclear hormone receptor superfamily that includes receptors for steroids, retinoids, and thyroid hormone, all of which are known to affect the immune response. Previous studies dealing with PPAR-γ expression in the immune system have been limited. Recently, PPAR-γ was identified in monocyte/macrophages. Here, the authors examd. the role of PPAR-γ in exptl. autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. The hypothesis the authors are testing is whether PPAR-γ plays an important role in EAE pathogenesis and whether PPAR-γ ligands can inhibit the clin. expression of EAE. Initial studies have shown that the presence of the PPAR-γ ligand 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) inhibits the proliferation of Ag-specific T cells from the spleen of myelin basic protein Ac1-11 TCR-transgenic mice. 15D-PGJ2 suppressed IFN-γ, IL-10, and IL-4 prodn. by both Con A- and myelin basic protein Ac1-11 peptide-stimulated lymphocytes as detd. by ELISA and ELISPOT assay. Culture of encephalitogenic T cells with 15d-PGJ2 in the presence of Ag reduced the ability of these cells to adoptively transfer EAE. Examn. of the target organ, the CNS, during the course of EAE revealed expression of PPAR-γ in the spinal cord inflammatory infiltrate. Administration of 15d-PGJ2 before and at the onset of clin. signs of EAE reduced the severity of disease. Thus, PPAR-γ ligands may be a novel therapeutic agent for diseases such as multiple sclerosis.
- 91Diab, A.; Hussain, R. Z.; Lovett-Racke, A. E.; Chavis, J. A.; Drew, P. D.; Racke, M. K. Ligands for the Peroxisome Proliferator-Activated Receptor-γ and the Retinoid X Receptor Exert Additive Anti-Inflammatory Effects on Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 2004, 148 (1–2), 116– 126, DOI: 10.1016/j.jneuroim.2003.11.010[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXht1yksb8%253D&md5=8d1bd671a66d35d5786ee5fa5c5f6fecLigands for the peroxisome proliferator-activated receptor-γ and the retinoid X receptor exert additive anti-inflammatory effects on experimental autoimmune encephalomyelitisDiab, Asim; Hussain, Rehana Z.; Lovett-Racke, Amy E.; Chavis, Janet A.; Drew, Paul D.; Racke, Michael K.Journal of Neuroimmunology (2004), 148 (1-2), 116-126CODEN: JNRIDW; ISSN:0165-5728. (Elsevier Science B.V.)Peroxisome proliferator-activated receptor-gamma (PPAR-γ) is a member of the nuclear-receptor superfamily that binds to DNA with retinoid x receptors (RXRs) as PPAR-RXR heterodimers. In exptl. autoimmune encephalomyelitis (EAE), the gene expression of PPAR-γ was demonstrated in spinal cord during the course of EAE. Administration of 15-deoxy-12,14-prostaglandin J2 (15d-PGJ2) or 9-cis-retinoic acid (RA) alone at the onset of clin. signs of EAE reduced the severity of disease, however, their combination resulted in enhanced amelioration of disease. These results suggest that use of RXR specific ligands may be highly effective when combined with PPAR-γ agonists in the treatment of autoimmune demyelinating diseases such as multiple sclerosis (MS).
- 92Bernardo, A.; Giammarco, M. L.; De Nuccio, C.; Ajmone-Cat, M. A.; Visentin, S.; De Simone, R.; Minghetti, L. Docosahexaenoic Acid Promotes Oligodendrocyte Differentiation via PPAR-γ Signalling and Prevents Tumor Necrosis Factor-α-Dependent Maturational Arrest. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2017, 1862 (9), 1013– 1023, DOI: 10.1016/j.bbalip.2017.06.014[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFSit7vO&md5=0bf4ccaceef726be5cfa3d5f06731876Docosahexaenoic acid promotes oligodendrocyte differentiation via PPAR-γ signalling and prevents tumor necrosis factor-α-dependent maturational arrestBernardo, A.; Giammarco, M. L.; De Nuccio, C.; Ajmone-Cat, M. A.; Visentin, S.; De Simone, R.; Minghetti, L.Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2017), 1862 (9), 1013-1023CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B.V.)Docosahexaenoic acid (DHA) is an essential omega-3 fatty acid known to be neuroprotective in several models of human diseases, including multiple sclerosis. The protective effects of DHA are largely attributed to its ability to interfere with the activity of transcription factors controlling immune and inflammatory responses, including the agonist-dependent transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ). In this study, we used primary oligodendrocyte progenitor (OP) cultures from neonatal rat brain to investigate whether DHA could influence OP maturation and directly promote myelination, as previously reported for selective PPAR-γ agonists. We show that, similarly to the selective PPAR-γ agonist pioglitazone (PGZ), DHA promotes OP maturation and counteracts the maturational arrest induced by TNF-α, used to mimic inflammatory conditions. The PPAR-γ antagonist GW9662 prevented both DHA-induced OP maturation and PPAR-γ nuclear translocation, supporting the hypothesis that DHA acts through the activation of PPAR-γ. In addn., both PGZ and DHA induced the phosphorylation of extracellular signal-regulated-kinase 1-2 (ERK1/2), in a PPAR-γ-dependent manner. ERK1/2 activity is known to regulate the transition from OPs to immature oligodendrocytes and the presence of specific inhibitors of ERK1/2 phosphorylation (U0126 or PD98059) prevented the differentiating effects of both DHA and PGZ. These results indicate that DHA might influence the process of OP maturation through its PPAR-γ agonistic activity and provide novel mol. mechanisms for the action of this dietary fatty acid, further supporting the nutritional intervention in demyelinating diseases such as multiple sclerosis.
- 93De Nuccio, C.; Bernardo, A.; Cruciani, C.; De Simone, R.; Visentin, S.; Minghetti, L. Peroxisome Proliferator Activated Receptor-γ Agonists Protect Oligodendrocyte Progenitors against Tumor Necrosis Factor-Alpha-Induced Damage: Effects on Mitochondrial Functions and Differentiation. Exp. Neurol. 2015, 271, 506– 514, DOI: 10.1016/j.expneurol.2015.07.014[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Ogs7rL&md5=dd69f6647de2b9d99c16bfa43b53d050Peroxisome proliferator activated receptor-γ agonists protect oligodendrocyte progenitors against tumor necrosis factor-alpha-induced damage: Effects on mitochondrial functions and differentiationDe Nuccio, C.; Bernardo, A.; Cruciani, C.; De Simone, R.; Visentin, S.; Minghetti, L.Experimental Neurology (2015), 271 (), 506-514CODEN: EXNEAC; ISSN:0014-4886. (Elsevier Inc.)The activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is known to exert anti-inflammatory and neuroprotective effects and PPAR-γ agonists are considered potential therapeutic agents in brain diseases including those affecting myelin. In demyelinating diseases such as multiple sclerosis (MS), inflammation is one of the causes of myelin and axonal damage. Oligodendrocyte (OL) differentiation is highly dependent on mitochondria, which are major targets of inflammatory insult. Here we show that PPAR-γ agonists protect OL progenitors against the maturational arrest induced by the inflammatory cytokine TNF-α by affecting mitochondrial functions. We demonstrate that the inhibition of OL differentiation by TNF-α is assocd. with (i) increased mitochondrial superoxide prodn.; (ii) decreased mitochondrial membrane potential (mMP); and (iii) decreased ADP-induced Ca2 + oscillations, which we previously showed to be dependent on efficient mitochondria. The TNF-α effects were comparable to those of the mitochondrial toxin rotenone, further suggesting that TNF-α damage is mediated by mitochondrial function impairment. PPAR-γ agonists protected OL progenitors against the inhibitory activities of both TNF-α and rotenone on mMP, mitochondrial ROS prodn., Ca2+ oscillations and OL differentiation. Finally, the PPAR-γ agonist pioglitazone increased the expression of PGC-1α (a mitochondrial biogenesis master regulator), UCP2 (a mitochondrial protein known to reduce ROS prodn.), and cytochrome oxidase subunit COX1. These findings confirm the central role of mitochondria in OL differentiation and point to mitochondria as major targets of PPAR-γ agonist protection against TNF-α damage.
- 94Storer, P. D.; Xu, J.; Chavis, J.; Drew, P. D. Peroxisome Proliferator-Activated Receptor-Gamma Agonists Inhibit the Activation of Microglia and Astrocytes: Implications for Multiple Sclerosis. J. Neuroimmunol. 2005, 161 (1–2), 113– 122, DOI: 10.1016/j.jneuroim.2004.12.015[Crossref], [PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhvVCjtbk%253D&md5=ddc6b561e337cbf0ee09d7a4bc546004Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: Implications for multiple sclerosisStorer, Paul D.; Xu, Jihong; Chavis, Janet; Drew, Paul D.Journal of Neuroimmunology (2005), 161 (1-2), 113-122CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)Peroxisome proliferator-activated receptor (PPAR)-γ agonists, including thiazolidinediones (TZDs) and 15-deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2), have been shown to be effective in the treatment of exptl. autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). This study aimed to compare the anti-inflammatory actions of three TZDs - rosiglitazone, pioglitazone, and ciglitazone - with those of 15d-PGJ2 on stimulated mouse microglia and astrocytes. The results show that TZDs and 15d-PGJ2 are effective in inhibiting prodn. of nitric oxide, the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, and the chemokine MCP-1 from microglia and astrocytes. However, 15d-PGJ2 was a more potent suppressor of pro-inflammatory activity than the TZDs. These studies suggest that PPAR-γ agonists modulate EAE, at least in part, by inhibiting the activation of microglia and astrocytes. The studies further suggest that PPAR-γ agonists may be effective in the treatment of MS.
- 95Zhang, F.; Liu, F.; Yan, M.; Ji, H.; Hu, L.; Li, X.; Qian, J.; He, X.; Zhang, L.; Shen, A.; Cheng, C. Peroxisome Proliferator-Activated Receptor-γ Agonists Suppress INOS Expression Induced by LPS in Rat Primary Schwann Cells. J. Neuroimmunol. 2010, 218 (1–2), 36– 47, DOI: 10.1016/j.jneuroim.2009.10.016[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtlyrtg%253D%253D&md5=61703c8257cd0c29eb7300445325ddc5Peroxisome proliferator-activated receptor-γ agonists suppress iNOS expression induced by LPS in rat primary Schwann cellsZhang, Fupeng; Liu, Fen; Yan, Meijuan; Ji, Huoyan; Hu, Ling; Li, Xiaohong; Qian, Ji; He, Xingxin; Zhang, Li; Shen, Aiguo; Cheng, ChunJournal of Neuroimmunology (2010), 218 (1-2), 36-47CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)In bacterial-induced peripheral nervous system (PNS) inflammation, Schwann cells (SCs) are activated, producing inducible nitric oxide synthase (iNOS), contributed to the pathogenesis of demyelinating disease, such as multiple sclerosis. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) has been shown to play a protective role in cellular inflammatory responses. Here the authors showed that LPS-induced iNOS biosynthesis was in a concn. and time-dependent manner. In LPS-treated primary SCs, re-treatment with PPAR-γ agonist remitted the increase of iNOS, p38 phosphorylation and TLR4, MyD88, augmented the expression of PPAR-γ and localization in nuclear. Coadministration of GW 9662 reversed the effect of PPAR-γ agonists. These results suggest that PPAR-γ agonists, 15d-PGJ2 and pioglitazone, had the anti-inflammatory effects.
- 96Grajchen, E.; Wouters, E.; Van De Haterd, B.; Haidar, M.; Hardonnière, K.; Dierckx, T.; Van Broeckhoven, J.; Erens, C.; Hendrix, S.; Kerdine-Römer, S.; Hendriks, J. J. A.; Bogie, J. F. J. CD36-Mediated Uptake of Myelin Debris by Macrophages and Microglia Reduces Neuroinflammation. J. Neuroinflammation 2020, 17, 224, DOI: 10.1186/s12974-020-01899-x[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFSitrnJ&md5=ae51e4155d73f19f3005bef24cb23b9bCD36-mediated uptake of myelin debris by macrophages and microglia reduces neuroinflammationGrajchen, Elien; Wouters, Elien; van de Haterd, Britt; Haidar, Mansour; Hardonniere, Kevin; Dierckx, Tess; Van Broeckhoven, Jana; Erens, Celine; Hendrix, Sven; Kerdine-Romer, Saadia; Hendriks, Jerome J. A.; Bogie, Jeroen F. J.Journal of Neuroinflammation (2020), 17 (1), 224CODEN: JNOEB3; ISSN:1742-2094. (BioMed Central Ltd.)The presence of foamy macrophages and microglia contg. intracellular myelin remnants is a pathol. hallmark of neurodegenerative disorders such as multiple sclerosis (MS). Despite the importance of myelin internalization in affecting both central nervous system repair and neuroinflammation, the receptors involved in myelin clearance and their impact on the phagocyte phenotype and lesion progression remain to be clarified. Flow cytometry, quant. PCR, and immunohistochem. were used to define the mRNA and protein abundance of CD36 in myelin-contg. phagocytes. The impact of CD36 and nuclear factor erythroid 2-related factor 2 (NRF2) on the phagocytic and inflammatory features of macrophages and microglia was assessed using a pharmacol. CD36 inhibitor (sulfo-N-succinimidyl oleate) and Nrf2-/- bone marrow-derived macrophages. Finally, the exptl. autoimmune encephalomyelitis (EAE) model was used to establish the impact of CD36 inhibition on neuroinflammation and myelin phagocytosis in vivo. Here, we show that the fatty acid translocase CD36 is required for the uptake of myelin debris by macrophages and microglia, and that myelin internalization increased CD36 expression through NRF2. Pharmacol. inhibition of CD36 promoted the inflammatory properties of myelin-contg. macrophages and microglia in vitro, which was paralleled by a reduced activity of the anti-inflammatory lipid-sensing liver X receptors and peroxisome proliferator-activated receptors. By using the EAE model, we provide evidence that CD36 is essential for myelin debris clearance in vivo. Importantly, CD36 inhibition markedly increased the neuroinflammatory burden and disease severity in the EAE model. Altogether, we show for the first time that CD36 is crucial for clearing myelin debris and suppressing neuroinflammation in demyelinating disorders such as MS.
- 97Schmidt, S.; Moric, E.; Schmidt, M.; Sastre, M.; Feinstein, D. L.; Heneka, M. T. Anti-Inflammatory and Antiproliferative Actions of PPAR-γ Agonists on T Lymphocytes Derived from MS Patients. J. Leukocyte Biol. 2004, 75 (3), 478– 485, DOI: 10.1189/jlb.0803402[Crossref], [PubMed], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXis1ehs7s%253D&md5=00d6f031765057f7e72be94b36e28365Anti-inflammatory and antiproliferative actions of PPAR-γ agonists on T lymphocytes derived from MS patientsSchmidt, Stephan; Moric, Edin; Schmidt, Martina; Sastre, Magdalena; Feinstein, Douglas L.; Heneka, Michael T.Journal of Leukocyte Biology (2004), 75 (3), 478-485CODEN: JLBIE7; ISSN:0741-5400. (Federation of American Societies for Experimental Biology)Peroxisomal proliferator-activated receptors (PPARs) belong to a nuclear receptor superfamily of ligand-activated transcription factors. The PPAR-γ isoform is expressed in human T lymphocytes, and oral administration of PPAR-γ agonists ameliorates the clin. course and histopathol. features in exptl. autoimmune encephalomyelitis, an animal model for multiple sclerosis, suggesting a potential role for PPAR-γ agonists in the treatment of autoimmune diseases. To assess a potential therapeutic role of PPAR-γ agonists in multiple sclerosis, we compared the immunomodulatory effects of the thiazolidinedione (TZD) drugs pioglitazone (PIO) and ciglitazone and the non-TZD PPAR-γ agonist GW347845 on human T leukemia cells (Jurkat cells) and phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) derived from 21 multiple sclerosis patients and 12 healthy donors. PIO, ciglitazone, and GW347845 suppressed PHA-induced T cell proliferation by 40-50% and secretion of interferon-γ and tumor necrosis factor α, by 30-50%. Inhibition of proliferation was increased to ∼80% and that of proinflammatory cytokine secretion, to 80-90% when PBMCs were first preincubated with PPAR-γ agonists and re-exposed at the time of PHA stimulation, indicating a sensitizing effect of PPAR-γ agonists. Inhibition of proliferation was also obsd. in the tetanus toxoid-specific T cell line KHS.TT2, albeit to a lesser extent. The antiproliferative effects of PIO and GW347845 were accompanied by a decrease of cell viability. Electron microscopy and Western blot anal. revealed DNA condensation and down-regulation of bcl-2, suggesting the induction of apoptosis in activated T lymphocytes. In summary, the data support the potential use of PPAR-γ agonists as immunomodulatory, therapeutic agents for autoimmune diseases.
- 98Polak, P. E.; Kalinin, S.; Dello Russo, C.; Gavrilyuk, V.; Sharp, A.; Peters, J. M.; Richardson, J.; Willson, T. M.; Weinberg, G.; Feinstein, D. L. Protective Effects of a Peroxisome Proliferator-Activated Receptor-β/δ Agonist in Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 2005, 168 (1–2), 65– 75, DOI: 10.1016/j.jneuroim.2005.07.006[Crossref], [PubMed], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVynt7bJ&md5=6cfd07b1f8b870cf47361a68e1758c12Protective effects of a peroxisome proliferator-activated receptor-β/δ agonist in experimental autoimmune encephalomyelitisPolak, Paul E.; Kalinin, Sergey; Dello Russo, Cinzia; Gavrilyuk, Vitaliy; Sharp, Anthony; Peters, Jeffrey M.; Richardson, Jill; Willson, Tim M.; Weinberg, Guy; Feinstein, Douglas L.Journal of Neuroimmunology (2005), 168 (1-2), 65-75CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)Agonists of the peroxisome proliferator-activated receptor gamma (PPARγ) exert anti-inflammatory and anti-proliferative effects which led to testing of these drugs in exptl. autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. In contrast, the effect of PPAR delta (PPARδ) agonists in EAE is not yet known. We show that oral administration of the selective PPARδ agonist GW0742 reduced clin. symptoms in C57BL/6 mice that had been immunized with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide. In contrast to previous results with PPARγ agonists, GW0742 only modestly attenuated clin. symptoms when the drug was provided simultaneously with immunization, but a greater redn. was obsd. if administered during disease progression. Reduced clin. symptoms were accompanied by a redn. in the appearance of new cortical lesions, however cerebellar lesion load was not reduced. Treatment of T-cells with GW0742 either in vivo or in vitro did not reduce IFNγ prodn.; however GW0742 reduced astroglial and microglial inflammatory activation and IL-1β levels in EAE brain. RTPCR anal. showed that GW0742 increased expression of some myelin genes. These data demonstrate that PPARδ agonists, like other PPAR ligands, can exert protective actions in an autoimmune model of demyelinating disease.
- 99Kanakasabai, S.; Walline, C. C.; Chakraborty, S.; Bright, J. J. PPARδ Deficient Mice Develop Elevated Th1/Th17 Responses and Prolonged Experimental Autoimmune Encephalomyelitis. Brain Res. 2011, 1376, 101– 112, DOI: 10.1016/j.brainres.2010.12.059[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhvFektLc%253D&md5=0ff2f2283a6aff09c3c0e9a5f0c59d2cPPARδ deficient mice develop elevated Th1/Th17 responses and prolonged experimental autoimmune encephalomyelitisKanakasabai, Saravanan; Walline, Crystal C.; Chakraborty, Sharmistha; Bright, John J.Brain Research (2011), 1376 (), 101-112CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)Multiple sclerosis (MS) is a neurol. disorder that affects more than a million people worldwide. The etiol. of MS is not known and there is no medical treatment that can cure MS. Earlier studies have shown that peroxisome proliferator-activated receptor (PPARs) agonists ameliorate MS-like disease in exptl. allergic encephalomyelitis (EAE). In this study the authors have used PPARδ deficient mice to det. its physiol. role in the regulation of CNS EAE and MS. The authors found that PPARδ-/- mice develop EAE with similar day of onset and disease incidence compared to C57BL/6 wild type mice. Interestingly, both male and female PPARδ-/- mice showed prolonged EAE with resistance to remission and recovery. PPARδ-/- mice with EAE expressed elevated levels of IFNγ and IL-17 along with IL-12p35 and IL-12p40 in the brain and spleen. PPARδ-/- mice also developed augmented neural antigen-specific Th1/Th17 responses and impaired Th2/Treg responses compared to wild type mice. These findings indicate that PPARδ-/- mice develop prolonged EAE in assocn. with augmented Th1/Th17 responses, suggesting a crit. physiol. role for PPARδ in the remission and recovery of EAE.
- 100Defaux, A.; Zurich, M. G.; Braissant, O.; Honegger, P.; Monnet-Tschudi, F. Effects of the PPAR-β Agonist GW501516 in an in Vitro Model of Brain Inflammation and Antibody-Induced Demyelination. J. Neuroinflammation 2009, 6, 15, DOI: 10.1186/1742-2094-6-15[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MzntlGguw%253D%253D&md5=ce8d6428111ad1e56400c1ae04293d95Effects of the PPAR-beta agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelinationDefaux Antoinette; Zurich Marie-Gabrielle; Braissant Olivier; Honegger Paul; Monnet-Tschudi FlorianneJournal of neuroinflammation (2009), 6 (), 15 ISSN:.BACKGROUND: Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-beta seems to play an important role in the regulation of central inflammation. In addition, PPAR-beta agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-beta agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-gamma and LPS. METHODS: Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-gamma and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG). The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), inducible NO synthase (i-NOS), PPAR-beta, PPAR-gamma, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and high molecular weight neurofilament protein (NF-H). GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4) and ED1 labeling. RESULTS: GW 501516 decreased the IFN-gamma-induced up-regulation of TNF-alpha and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-beta agonist. However, it increased IL-6 m-RNA expression. In demyelinating cultures, reactivity of both microglial cells and astrocytes was observed, while the expression of the inflammatory cytokines and iNOS remained unaffected. Furthermore, GW 501516 did not protect against the demyelination-induced changes in gene expression. CONCLUSION: Although GW 501516 showed anti-inflammatory activity, it did not protect against antibody-mediated demyelination. This suggests that the protective effects of PPAR-beta agonists observed in vivo can be attributed to their anti-inflammatory properties rather than to a direct protective or trophic effect on oligodendrocytes.
- 101Kanakasabai, S.; Chearwae, W.; Walline, C. C.; Iams, W.; Adams, S. M.; Bright, J. J. Peroxisome Proliferator-Activated Receptor δ Agonists Inhibit T Helper Type 1 (Th1) and Th17 Responses in Experimental Allergic Encephalomyelitis. Immunology 2010, 130 (4), 572– 588, DOI: 10.1111/j.1365-2567.2010.03261.x[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvVWnsLc%253D&md5=efd42469ce5c7f751064c5a0b1d03029Peroxisome proliferator-activated receptor δ agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitisKanakasabai, Saravanan; Chearwae, Wanida; Walline, Crystal C.; Iams, Wade; Adams, Suzanne M.; Bright, John J.Immunology (2010), 130 (4), 572-588CODEN: IMMUAM; ISSN:0019-2805. (Wiley-Blackwell)Multiple sclerosis (MS) is a neurol. disorder that affects more than a million people world-wide. The etiol. of MS is not known and there is no medical treatment available that can cure MS. Exptl. autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease model of MS. The pathogenesis of EAE/MS is a complex process involving activation of immune cells, secretion of inflammatory cytokines and destruction of myelin sheath in the central nervous system (CNS). Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptor transcription factors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown that PPARγ, α and δ agonists inhibit CNS inflammation and demyelination in the EAE model of MS. In this study we show that the PPARδ agonists GW501516 and L165041 ameliorate MOGp35-55-induced EAE in C57BL/6 mice by blocking interferon (IFN)-γ and interleukin (IL)-17 prodn. by T helper type 1 (Th1) and Th17 cells. The inhibition of EAE by PPARδ agonists was also assocd. with a decrease in IL-12 and IL-23 and an increase in IL-4 and IL-10 expression in the CNS and lymphoid organs. These findings indicate that PPARδ agonists modulate Th1 and Th17 responses in EAE and suggest their use in the treatment of MS and other autoimmune diseases.
- 102Jana, M.; Mondal, S.; Gonzalez, F. J.; Pahan, K. Gemfibrozil, a Lipid-Lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-Activated Receptor-β. J. Biol. Chem. 2012, 287 (41), 34134– 34148, DOI: 10.1074/jbc.M112.398552[Crossref], [PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVKlsLjK&md5=c48696a5867211d0b2f69ac1ce28fe46Gemfibrozil, a Lipid-lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-activated Receptor-βJana, Malabendu; Mondal, Susanta; Gonzalez, Frank J.; Pahan, KalipadaJournal of Biological Chemistry (2012), 287 (41), 34134-34148CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis. Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identified another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (myelin basic protein, myelin oligodendrocyte glycoprotein, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, and proteolipid protein (PLP)) in primary human oligodendrocytes, mixed glial cells, and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-α (PPAR-α), we were unable to detect PPAR-α in either gemfibrozil-treated or untreated human oligodendrocytes, and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-α(-/-) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-β but not PPAR-γ. Consistently, antisense knockdown of PPAR-β, but not PPAR-γ, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not up-regulate myelin genes in oligodendroglia isolated from PPAR-β(-/-) mice. Chromatin immunopptn. anal. showed that gemfibrozil induced the recruitment of PPAR-β to the promoter of PLP and myelin oligodendrocyte glycoprotein genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-β to the PLP promoter in vivo in the spinal cord of exptl. autoimmune encephalomyelitis mice and suppression of exptl. autoimmune encephalomyelitis symptoms in PLP-T cell receptor transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-β and that gemfibrozil, a prescribed drug for humans, may find further therapeutic use in demyelinating diseases.
- 103Sakuma, S.; Endo, T.; Kanda, T.; Nakamura, H.; Yamasaki, S.; Yamakawa, T. Synthesis of a Novel Human PPARδ Selective Agonist and Its Stimulatory Effect on Oligodendrocyte Differentiation. Bioorg. Med. Chem. Lett. 2011, 21 (1), 240– 244, DOI: 10.1016/j.bmcl.2010.11.030[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Sqsb7J&md5=3a7d74f2f007c601a273b75699478f26Synthesis of a novel human PPARδ selective agonist and its stimulatory effect on oligodendrocyte differentiationSakuma, Shogo; Endo, Tsuyoshi; Kanda, Takashi; Nakamura, Hideki; Yamasaki, Satomi; Yamakawa, TomioBioorganic & Medicinal Chemistry Letters (2011), 21 (1), 240-244CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A novel peroxisome proliferator-activated receptor (PPAR)δ selective agonist with a characteristic benzisoxazole ring, I, was successfully synthesized. Compd. I exhibited potent human PPARδ transactivation activity and high δ selectivity. Further, it stimulated differentiation of primary oligodendrocyte precursor cells in vitro, indicating that it may be an effective drug in the treatment of demyelinating disorders such as multiple sclerosis.
- 104Kaiser, C. C.; Shukla, D. K.; Stebbins, G. T.; Skias, D. D.; Jeffery, D. R.; Stefoski, D.; Katsamakis, G.; Feinstein, D. L. A Pilot Test of Pioglitazone as an Add-on in Patients with Relapsing Remitting Multiple Sclerosis. J. Neuroimmunol. 2009, 211 (1–2), 124– 130, DOI: 10.1016/j.jneuroim.2009.04.011[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnt1Gktb0%253D&md5=e699f96e3ce6499a1430f31edeefb082A pilot test of pioglitazone as an add-on in patients with relapsing remitting multiple sclerosisKaiser, Claudia C.; Shukla, Dinesh K.; Stebbins, Glenn T.; Skias, Demetrios D.; Jeffery, Douglas R.; Stefoski, Dusan; Katsamakis, George; Feinstein, Douglas L.Journal of Neuroimmunology (2009), 211 (1-2), 124-130CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)The peroxisome proliferator-activated receptor gamma agonist pioglitazone is FDA-approved for treatment of type-2 diabetes due to insulin sensitizing effects. However pioglitazone has anti-inflammatory and neuroprotective effects, reduces glial and T-cell activation, and reduces signs in an animal model of multiple sclerosis (MS). We tested the effects of daily treatment with pioglitazone in a small cohort of relapsing remitting MS patients. RRMS patients taking IFNβ-1α and having an EDSS score < 6.5 were randomized to treatment with pioglitazone (30 mg daily, p.o.) or placebo and monitored clin. and by MRI for 1 yr. Primary outcomes were safety and tolerability, secondary outcomes included changes in neurol. outcome, lesion burden, and gray matter vol. After 1 yr 11 patients in the pioglitazone arm and 10 in the placebo arm completed the trial. Pioglitazone was well tolerated with a similar incidence of non-serious adverse events in placebo and treatment groups. After 1 yr there were no significant differences in clin. symptoms as assessed by EDSS; however MRI showed a significant redn. in gray matter atrophy, and a trend for reduced lesion burden in the treatment group. These results show that pioglitazone was well tolerated in RRMS patients with indications of beneficial effects, warranting further trials to establish clin. efficacy.
- 105Shukla, D. K.; Kaiser, C. C.; Stebbins, G. T.; Feinstein, D. L. Effects of Pioglitazone on Diffusion Tensor Imaging Indices in Multiple Sclerosis Patients. Neurosci. Lett. 2010, 472 (3), 153– 156, DOI: 10.1016/j.neulet.2010.01.046[Crossref], [PubMed], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjt1ers78%253D&md5=44355f921438e3ed0d58aace2043cf44Effects of pioglitazone on diffusion tensor imaging indices in multiple sclerosis patientsShukla, Dinesh K.; Kaiser, Claudia C.; Stebbins, Glenn T.; Feinstein, Douglas L.Neuroscience Letters (2010), 472 (3), 153-156CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Pioglitazone is an FDA-approved peroxisome proliferator activated receptor gamma (PPARγ) agonist. We tested the hypothesis that treatment with pioglitazone reduces new lesion development in patients with RRMS. Twenty-two patients were treated with pioglitazone or placebo and monitored by diffusion tensor imaging (DTI) at baseline and after 12 mo. A neg. correlation was found between the 1-yr change in relative anisotropy (RA) and fluid attenuated inversion recovery (FLAIR) lesion burden in the pioglitazone group. Regions of interest (ROIs) having high ADC and low RA values at baseline had a significantly higher chance to develop into lesions in the placebo group than similar ROIs in the pioglitazone group. These findings suggest that baseline DTI parameters can provide a prognostic surrogate marker for lesions, and that pioglitazone can reduce conversion of normal appearing white matter to lesions.
- 106Negrotto, L.; Farez, M. F.; Correale, J. Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis. JAMA Neurol. 2016, 73 (5), 520– 528, DOI: 10.1001/jamaneurol.2015.4807[Crossref], [PubMed], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28jotFCrug%253D%253D&md5=421d790edbbc6237084f3a13568705e1Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple SclerosisNegrotto Laura; Farez Mauricio F; Correale JorgeJAMA neurology (2016), 73 (5), 520-8 ISSN:.IMPORTANCE: Metabolic syndrome (MetS) is thought to influence several autoimmune diseases, including multiple sclerosis (MS). Anti-inflammatory effects of treatments used for MetS, such as metformin hydrochloride and pioglitazone hydrochloride, have been demonstrated, although clinical evidence supporting use of these treatments in MS is lacking. OBJECTIVES: To determine whether metformin and/or pioglitazone are associated with a reduction in disease activity as measured by brain magnetic resonance imaging in patients with MS and MetS and to evaluate the potential mechanisms underlying this anti-inflammatory effect. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted from March 1, 2012, to December 30, 2014, at a private MS referral center among 50 obese patients with MS who also developed MetS. Twenty patients received metformin hydrochloride, 850 to 1500 mg/d, and 10 patients received pioglitazone hydrochloride, 15 to 30 mg/d; 20 untreated patients served as controls. Groups were comparable in terms of sex, age, body mass index, Expanded Disability Status Scale score, disease duration, annual relapse rate, and treatment status. Patients were followed up for a mean (SD) of 26.7 (2.7) months (range, 24-33 months). MAIN OUTCOMES AND MEASURES: Magnetic resonance imaging of the brain was performed at 6-month intervals, and the presence of new or enlarging T2 lesions or gadolinium-enhancing lesions was registered. Serum leptin and adiponectin levels were measured. The production of cytokines by peripheral blood mononuclear cells was assayed, as were regulatory T-cell numbers and function. RESULTS: Of 50 patients, after 6 months of treatment, 20 patients with MS who were treated with metformin and 10 who received pioglitazone showed a significant decrease in the number of new or enlarging T2 lesions (metformin, 2.5 at study entry to 0.5 at month 24; pioglitazone, 2.3 at study entry to 0.6 at month 24), as well as of gadolinium-enhancing lesions (metformin, 1.8 at study entry to 0.1 at month 24; pioglitazone, 2.2 at study entry to 0.3 at month 24). Compared with controls, both treatments led to a decrease in mean (SD) leptin levels (metformin, 5.5 [2.4] vs 10.5 [3.4] ng/mL, P < .001; pioglitazone, 4.1 [0.8] vs 11.0 [2.6] ng/mL, P < .001) and increase in mean (SD) adiponectin serum levels (metformin, 15.4 [5.5] vs 4.5 [2.4] μg/mL, P < .001; pioglitazone, 12.6 [3.6] vs 4.8 [0.6] μg/mL, P < .001). Mean (SD) number of myelin basic protein peptide-specific cells secreting interferon γ and interleukin (IL)-17 were significantly reduced in patients receiving metformin compared with controls (interferon γ, 30.3 [11.5] vs 82.8 [18.8], P < .001; IL-17, 212.4 [85.5] vs 553.8 [125.9], P < .001). Patients treated with pioglitazone showed significant decreases in the mean (SD) number of myelin basic protein peptide-specific cells secreting IL-6 and tumor necrosis factor compared with controls (IL-6, 361.6 [80.5] vs 1130.7 [149.21], P < .001; tumor necrosis factor, 189.9 [53.4] vs 341.0 [106.0], P < .001). Both metformin and pioglitazone resulted in a significant increase in the number and regulatory functions of CD4+CD25+FoxP3+ regulatory T cells compared with controls (metformin, 6.7 [1.5] vs 2.1 [1.0], P = .001; pioglitazone, 6.9 [0.8] vs 3.0 [0.8], P = .001). CONCLUSIONS AND RELEVANCE: Treatment with metformin and pioglitazone has beneficial anti-inflammatory effects in patients with MS and MetS and should be further explored.
- 107Ratziu, V.; Harrison, S. A.; Francque, S.; Bedossa, P.; Lehert, P.; Serfaty, L.; Romero-Gomez, M.; Boursier, J.; Abdelmalek, M.; Caldwell, S.; Drenth, J.; Anstee, Q. M.; Hum, D.; Hanf, R.; Roudot, A.; Megnien, S.; Staels, B.; Sanyal, A. Elafibranor, an Agonist of the Peroxisome Proliferator–Activated Receptor−α and – δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology 2016, 150 (5), 1147– 1159, DOI: 10.1053/j.gastro.2016.01.038[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xms1Klu7g%253D&md5=cee5c53be700bd0a9eadb455390a222cElafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis WorseningRatziu, Vlad; Harrison, Stephen A.; Francque, Sven; Bedossa, Pierre; Lehert, Philippe; Serfaty, Lawrence; Romero-Gomez, Manuel; Boursier, Jerome; Abdelmalek, Manal; Caldwell, Steve; Drenth, Joost; Anstee, Quentin M.; Hum, Dean; Hanf, Remy; Roudot, Alice; Megnien, Sophie; Staels, Bart; Sanyal, ArunGastroenterology (2016), 150 (5), 1147-1159.e5CODEN: GASTAB; ISSN:0016-5085. (Elsevier)Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-δ. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metab. and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with nonalcoholic steatohepatitis (NASH). Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n = 93), elafibranor 120 mg (n = 91), or placebo (n = 92) each day for 52 wk at sites in Europe and the United States. Clin. and lab. evaluations were performed every 2 mo during this 1-yr period. Liver biopsies were then collected and patients were assessed 3 mo later. The primary outcome was resoln. of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver disease activity score. In intention-to-treat anal., there was no significant difference between the elafibranor and placebo groups in the protocol-defined primary outcome. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranor group vs the placebo group (19% vs 12%; odds ratio = 2.31; 95% confidence interval: 1.02-5.24; P = .045), based on a post-hoc anal. for the modified definition. In post-hoc analyses of patients with nonalcoholic fatty liver disease activity score ≥4 (n = 234), elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; odds ratio = 3.16; 95% confidence interval: 1.22-8.13; P = .018) and the modified definitions (19% vs 9%; odds ratio = 3.52; 95% confidence interval: 1.32-9.40; P = .013). Patients with NASH resoln. after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resoln. (mean redn. of 0.65 ± 0.61 in responders for the primary outcome vs an increase of 0.10 ± 0.98 in nonresponders; P < .001). Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group vs the placebo group. Elafibranor was well tolerated and did not cause wt. gain or cardiac events, but did produce a mild, reversible increase in serum creatinine (effect size vs placebo: increase of 4.31 ± 1.19 μmol/L; P < .001). A post-hoc anal. of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 yr) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat anal. and in patients with moderate or severe NASH. However, the predefined end point was not met in the intention to treat population. Elafibranor was well tolerated and improved patients' cardiometabolic risk profile. ClinicalTrials.gov no.: NCT01694849.
- 108Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown, K. K.; Cobb, J. E.; Collins, J. L.; Harrington, W. W.; Hashim, M. A.; Hull-Ryde, E. A.; Kaldor, I.; Kliewer, S. A.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J. M.; Lenhard, J. M.; Orband-Miller, L. A.; Miller, J. F.; Mook, R. A.; Noble, S. A.; Oliver, W.; Parks, D. J.; Plunket, K. D.; Szewczyk, J. R.; Willson, T. M. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 1. Discovery of a Novel Series of Potent Antihyperglycemic and Antihyperlipidemic Agents. J. Med. Chem. 1998, 41 (25), 5020– 5036, DOI: 10.1021/jm9804127[ACS Full Text], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntF2ru7w%253D&md5=712246afde03c871a967800db615ba9fN-(2-Benzoylphenyl)-L-tyrosine PPARγ Agonists. 1. Discovery of a Novel Series of Potent Antihyperglycemic and Antihyperlipidemic AgentsHenke, Brad R.; Blanchard, Steven G.; Brackeen, Marcus F.; Brown, Kathleen K.; Cobb, Jeff E.; Collins, Jon L.; Harrington, W. Wallace, Jr.; Hashim, Mir A.; Hull-Ryde, Emily A.; Kaldor, Istvan; Kliewer, Steven A.; Lake, Debra H.; Leesnitzer, Lisa M.; Lehmann, Juergen M.; Lenhard, James M.; Orband-Miller, Lisa A.; Miller, John F.; Mook, Robert A.; Noble, Stewart A.; Oliver, William; Parks, Derek J.; Plunket, Kelli D.; Szewczyk, Jerzy R.; Willson, Timothy M.Journal of Medicinal Chemistry (1998), 41 (25), 5020-5036CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivs. which are potent, selective PPARγ agonists. Through the use of in vitro PPARγ binding and functional assays, (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)amino)propionic acid (I) was identified as a structurally novel PPARγ agonist. Structure-activity relationships identified the 2-aminobenzophenone moiety as a suitable isostere for the chem. labile enaminone moiety in I, affording 2-((2-benzoylphenyl)amino)-3-(4-(benzyloxy)phenyl)propionic acid. Replacement of the benzyl group in 9 with substituents known to confer in vivo potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARγ, affording a series of potent and selective PPARγ agonists exemplified by (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(methylpyridin-2-ylamino)ethoxy]phenyl}propionic acid (II), 3-{4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl}-(2S)-((2-benzoylphenyl)amino)propanoic acid, and (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic acid (III). II and III show potent antihyperglycemic and antihyperlipidemic activity when given orally in two rodent models of type 2 diabetes. In addn., these analogs are readily prepd. in chiral nonracemic fashion from L-tyrosine and do not show a propensity to undergo racemization in vitro. The increased potency of these PPARγ agonists relative to troglitazone may translate into superior clin. efficacy for the treatment of type 2 diabetes.
- 109Cobb, J. E.; Blanchard, S. G.; Boswell, E. G.; Brown, K. K.; Charifson, P. S.; Cooper, J. P.; Collins, J. L.; Dezube, M.; Henke, B. R.; Hull-Ryde, E. A.; Lake, D. H.; Lenhard, J. M.; Oliver, W.; Oplinger, J.; Pentti, M.; Parks, D. J.; Plunket, K. D.; Tong, W.-Q. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 3. Structure-Activity Relationship and Optimization of the N-Aryl Substituent. J. Med. Chem. 1998, 41 (25), 5055– 5069, DOI: 10.1021/jm980414r[ACS Full Text], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntFegu74%253D&md5=c411bc54b96bdd80f365c2300572f7b1N-(2-Benzoylphenyl)-L-tyrosine PPARγ Agonists. 3. Structure-Activity Relationship and Optimization of the N-Aryl SubstituentCobb, Jeff E.; Blanchard, Steven G.; Boswell, Evan G.; Brown, Kathleen K.; Charifson, Paul S.; Cooper, Joel P.; Collins, Jon L.; Dezube, Milana; Henke, Brad R.; Hull-Ryde, Emily A.; Lake, Debra H.; Lenhard, James M.; Oliver, William, Jr.; Oplinger, Jeffery; Pentti, Mila; Parks, Derek J.; Plunket, Kelli D.; Tong, Wei-QinJournal of Medicinal Chemistry (1998), 41 (25), 5055-5069CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)3-{4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl}-(2S)-((2-benzoylphenyl)amino)propionic acid (I) and (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid (II) are peroxisome proliferator-activated receptor γ (PPARγ) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of I and II, a series of novel carboxylic acid analogs, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARγ agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of I and II are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two Ph rings of this moiety. Addn. of substituents to this moiety generally produced compds. that are less active in the cell-based functional assays of PPARγ activity although binding affinity to PPARγ may be maintained. A particularly promising set of analogs is the anthranilic acid esters in which the Ph ring in the 2-benzoyl group of I and II has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid Me ester (III) has a pKi of 8.43 in the binding assay using human PPARγ ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARγ activity. Finally, III was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.
- 110Collins, J. L.; Blanchard, S. G.; Boswell, G. E.; Charifson, P. S.; Cobb, J. E.; Henke, B. R.; Hull-Ryde, E. A.; Kazmierski, W. M.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J.; Lenhard, J. M.; Orband-Miller, L. A.; Gray-Nunez, Y.; Parks, D. J.; Plunkett, K. D.; Tong, W.-Q. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 2. Structure-Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety. J. Med. Chem. 1998, 41 (25), 5037– 5054, DOI: 10.1021/jm980413z[ACS Full Text], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntFegurc%253D&md5=10c2016d15446cb8bfa5d1eba6a2558bN-(2-Benzoylphenyl)-L-tyrosine PPARγ Agonists. 2. Structure-Activity Relationship and Optimization of the Phenyl Alkyl Ether MoietyCollins, Jon L.; Blanchard, Steven G.; Boswell, G. Evan; Charifson, Paul S.; Cobb, Jeff E.; Henke, Brad R.; Hull-Ryde, Emily A.; Kazmierski, Wieslaw M.; Lake, Debra H.; Leesnitzer, Lisa M.; Lehmann, Juergen; Lenhard, James M.; Orband-Miller, Lisa A.; Gray-Nunez, Yolanda; Parks, Derek J.; Plunkett, Kelli D.; Tong, Wei-QinJournal of Medicinal Chemistry (1998), 41 (25), 5037-5054CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic acid (I) (PPARγ pKi = 8.94, PPARγ pEC50 = 9.47) as a potent and selective PPARγ agonist. We now report the expanded structure-activity relationship around the Ph alkyl ether moiety by pursuing both a classical medicinal chem. approach and a solid-phase chem. approach for analog synthesis. The soln.-phase strategy focused on evaluating the effects of oxazole and Ph ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of I with several replacements providing potent and selective PPARγ agonists with improved aq. soly. Specifically, replacement of the Ph ring of the phenyloxazole moiety with a 4-pyridyl group to give (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-pyridin-4-yloxazol-4-yl)ethoxy]phenyl}propionic acid (PPARγ pKi = 8.85, PPARγ pEC50 = 8.74) or a 4-methylpiperazine to give (2S)-((2-benzoylphenyl)amino)-3-(4-{2-[5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl]ethoxy}phenyl)propionic acid (PPARγ pKi = 8.66, PPARγ pEC50 = 8.89) provided two potent and selective PPARγ agonists with increased soly. in pH 7.4 phosphate buffer and simulated gastric fluid as compared to I. The second strategy took advantage of the speed and ease of parallel solid-phase analog synthesis to generate a more diverse set of Ph alkyl ethers which led to the identification of a no. of novel, high-affinity PPARγ ligands (PPARγ pKi's 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPARγ binding, functional activity, selectivity, and aq. soly.
- 111Berger, J.; Leibowitz, M. D.; Doebber, T. W.; Elbrecht, A.; Zhang, B.; Zhou, G.; Biswas, C.; Cullinan, C. A.; Hayes, N. S.; Li, Y.; Tanen, M.; Ventre, J.; Wu, M. S.; Berger, G. D.; Mosley, R.; Marquis, R.; Santini, C.; Sahoo, S. P.; Tolman, R. L.; Smith, R. G.; M?ller, D. E. Novel Peroxisome Proliferator-Activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects. J. Biol. Chem. 1999, 274 (10), 6718– 6725, DOI: 10.1074/jbc.274.10.6718[Crossref], [PubMed], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXhs1ektb0%253D&md5=c62b5d778386a81d91221d6330f8e8d3Novel peroxisome proliferator-activated receptor (PPAR) γ and PPARδ ligands produce distinct biological effectsBerger, Joel; Leibowitz, Mark D.; Doebber, Thomas W.; Elbrecht, Alex; Zhang, Bei; Zhou, Gaochou; Biswas, Chhabi; Cullinan, Catherine A.; Hayes, Nancy S.; Li, Ying; Tanen, Michael; Ventre, John; Wu, Margaret S.; Berger, Gregory D.; Mosley, Ralph; Marquis, Robert; Santini, Conrad; Sahoo, Soumya P.; Tolman, Richard L.; Smith, Roy G.; Moller, David E.Journal of Biological Chemistry (1999), 274 (10), 6718-6725CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The peroxisome proliferator-activated receptors (PPARs) include three receptor subtypes encoded by sep. genes: PPARα, PPARδ, and PPARγ. PPARγ has been implicated as a mediator of adipocyte differentiation and the mechanism by which thiazolidinedione drugs exert in vivo insulin sensitization. Here we characterized novel, non-thiazolidinedione agonists for PPARγy and PPARδ that were identified by radioligand binding assays. In transient transactivation assays these ligands were agonists of the receptors to which they bind. Protease protection studies showed that ligand binding produced specific alterations in receptor conformation. Both PPARγ and PPARδ directly interacted with a nuclear receptor co-activator (CREB-binding protein) in an agonist-dependent manner. Only the PPARγ agonists were able to promote differentiation of 3T3-L1 preadipocytes. In diabetic db/db mice all PPARγ agonists were orally active insulin-sensitizing agents producing redns. of elevated plasma glucose and triglyceride concns. In contrast, selective in vivo activation of PPARδ did not significantly affect these parameters. In vivo PPARα activation with WY-14653 resulted in redns. in elevated triglyceride levels with minimal effect on hyperglycemia. We conclude that: 1. synthetic non-thiazolidinediones can serve as ligands of PPARγ and PPARδ; 2. ligand-dependent activation of PPARδ involves an apparent conformational change and assocn. of the receptor ligand binding domain with CREB-binding protein; 3. PPARγ activation (but not PPARδ or PPARα activation) is sufficient to potentiate preadipocyte differentiation; 4. non-thiazolidinedione PPARγ agonists improve hyperglycemia and hypertriglyceridemia in vivo; 5. although PPARα activation is sufficient to affect triglyceride metab., PPARδ activation does not appear to modulate glucose or triglyceride levels.
- 112Brown, P. J.; Stuart, L. W.; Hurley, K. P.; Lewis, M. C.; Winegar, D. A.; Wilson, J. G.; Wilkison, W. O.; Ittoop, O. R.; Willson, T. M. Identification of a Subtype Selective Human PPARα Agonist through Parallel-Array Synthesis. Bioorg. Med. Chem. Lett. 2001, 11 (9), 1225– 1227, DOI: 10.1016/S0960-894X(01)00188-3[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjt1Witbo%253D&md5=8cddeedf8db5ade83ebe8e43ad5f6242Identification of a subtype selective human PPARα agonist through parallel-array synthesisBrown, P. J.; Stuart, L. W.; Hurley, K. P.; Lewis, M. C.; Winegar, D. A.; Wilson, J. G.; Wilkison, W. O.; Ittoop, O. R.; Willson, T. M.Bioorganic & Medicinal Chemistry Letters (2001), 11 (9), 1225-1227CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Using solid-phase, parallel-array synthesis, a series of urea-substituted thioisobutyric acids was synthesized and assayed for activity on the human PPAR subtypes. GW7647 (3) was identified as a potent human PPARα agonist with ∼200-fold selectivity over PPARγ and PPARδ, and potent lipid-lowering activity in animal models of dyslipidemia. GW7647 (3) will be a valuable chem. tool for studying the biol. of PPARα in human cells and animal models of disease. Using solid-phase, parallel-array synthesis, a series of urea-substituted thioisobutyric acids was synthesized. GW7647 (3) was identified as a potent, selective human PPARα agonist.
- 113Kane, C. D.; Stevens, K. A.; Fischer, J. E.; Haghpassand, M.; Royer, L. J.; Aldinger, C.; Landschulz, K. T.; Zagouras, P.; Bagley, S. W.; Hada, W.; Dullea, R.; Hayward, C. M.; Francone, O. L. Molecular Characterization of Novel and Selective Peroxisome Proliferator-Activated Receptor α Agonists with Robust Hypolipidemic Activity in Vivo. Mol. Pharmacol. 2009, 75 (2), 296– 306, DOI: 10.1124/mol.108.051656[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlGitr8%253D&md5=e35229c6ec18556e39fb3b2014ca6fa1Molecular characterization of novel and selective peroxisome proliferator-activated receptor α agonists with robust hypolipidemic activity in vivoKane, Christopher D.; Stevens, Kimberly A.; Fischer, James E.; Haghpassand, Mehrdad; Royer, Lori J.; Aldinger, Charles; Landschulz, Katherine T.; Zagouras, Panayiotis; Bagley, Scott W.; Hada, William; Dullea, Robert; Hayward, Cheryl M.; Francone, Omar L.Molecular Pharmacology (2009), 75 (2), 296-306CODEN: MOPMA3; ISSN:0026-895X. (American Society for Pharmacology and Experimental Therapeutics)The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARα agonists with therapeutic potential for treating dyslipidemia. These structurally related compds. display potent and selective binding to human PPARα and support robust recruitment of coactivator peptides in vitro. These compds. markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARα agonists were assessed by transcriptional profiling of mouse liver after short- and long-term treatment. The induction of several known PPARα target genes involved with fatty acid metab. were obsd., reflecting the expected pharmacol. assocd. with PPARα activation. We also noted the down-regulation of a no. of genes related to immune cell function, the acute phase response, and glucose metab., suggesting that these compds. may have anti-inflammatory action in the mammalian liver. Whereas these compds. are efficacious in acute preclin. models, extended safety studies and further clin. testing will be required before the full therapeutic promise of a selective PPARα agonist is realized.
- 114Kuwabara, K.; Murakami, K.; Todo, M.; Aoki, T.; Asaki, T.; Murai, M.; Yano, J. A Novel Selective Peroxisome Proliferator-Activated Receptor α Agonist, 2-Methyl-c-5-[4-[5-Methyl-2-(4-Methylphenyl)-4-Oxazolyl]Butyl]-1, 3-Dioxane-r-2-Carboxylic Acid (NS-220), Potently Decreases Plasma Triglyceride and Glucose Levels and Modifies Lipopr. J. Pharmacol. Exp. Ther. 2004, 309 (3), 970– 977, DOI: 10.1124/jpet.103.064659[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXksFCnsbg%253D&md5=d715ea8cfa76202e3f759fef97038c71A novel selective peroxisome proliferator-activated receptor α agonist, 2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), potently decreases plasma triglyceride and glucose levels and modifies lipoprotein profiles in KK-Ay miceKuwabara, Kenji; Murakami, Kohji; Todo, Makoto; Aoki, Tomiyoshi; Asaki, Tetsuo; Murai, Masatoshi; Yano, JunichiJournal of Pharmacology and Experimental Therapeutics (2004), 309 (3), 970-977CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)NS-220 was newly synthesized and demonstrated to be a novel potent peroxisome proliferator-activated receptor α (PPARα) agonist with high subtype selectivity. In cell-based reporter gene assays, the EC50 values of NS-220 for human PPARα, PPARγ, and PPARδ were 1.9×10-8, 9.6×10-6, and >10-4 M, resp., and for mouse PPARα, PPARγ, and PPARδ were 5.5×10-8, 3.3×10-5, and >10-4 M, resp. In addn., [3H]NS-220 bound to the ligand-binding domain of human PPARα with a KD value of 1.85×10-7 M. Fenofibric acid and bezafibrate showed weak agonist activity for PPARα (EC50, 2-8×10-5 M), with poor subtype selectivity. NS-220 (0.1-3 mg/kg p.o.) decreased plasma triglyceride levels in ddY mice in a dose-dependent manner, but its hypolipidemic activity was abolished in PPARα-deficient mice. In KK-Ay mice, an animal model of type-2 diabetes, NS-220 (0.3-1 mg/kg p.o.; 4 days) and fenofibrate (100-300 mg/kg p.o.; 4 days) decreased plasma triglyceride and glucose levels in a dose-dependent manner. In a 2-wk repeated administration test, NS-220 (0.3-1 mg/kg p.o.) decreased plasma glucose levels markedly without increasing in plasma insulin levels. Furthermore, NS-220 increased high-d. lipoprotein levels and decreased triglyceride-rich lipoprotein levels. In conclusion, a newly synthesized dioxanecarboxylic acid deriv., NS-220, is a potent and highly selective PPARα agonist that ameliorates metabolic disorders in diabetic mice. These results strongly suggest that it will be a promising drug for the treatment of hyperlipidemia or metabolic disorders in type-2 diabetes.
- 115Santilli, A. A.; Scotese, A. C.; Tomarelli, R. M. A Potent Antihypercholesterolemic Agent: [4-Chloro-6-(2,3-Xylidino)-2-Pyrimidinylthio]Acetic Acid (Wy-14643). Experientia 1974, 30 (10), 1110– 1111, DOI: 10.1007/BF01923636[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXmvVaqug%253D%253D&md5=f10efeb39397486a1b850abd711e7748Potent antihypercholesterolemic agent, [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14643)Santilli, A. A.; Scotese, A. C.; Tomarelli, R. M.Experientia (1974), 30 (10), 1110-11CODEN: EXPEAM; ISSN:0014-4754.Wy 14643 (I) [50892-23-4] (0.1-50 mg/day) lowered the blood serum cholesterol levels of rats with dietary hypercholesterolemia in a dose-related manner. I was more potent than clofibrate [637-07-0]. I was prepd. by alkylation of sodium 2-thiobarbiturate [31645-12-2] with ethyl bromoacetate [105-36-2], followed by chlorination and reaction of the resultant product with 2,3-dimethylaniline [87-59-2].
- 116Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. The PPARs: From Orphan Receptors to Drug Discovery. J. Med. Chem. 2000, 43, 527– 550, DOI: 10.1021/jm990554g[ACS Full Text], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXht1Churk%253D&md5=003b19fe3fdf813411d6a2ac5aefdc01The PPARs: From orphan receptors to drug discoveryWillson, Timothy M.; Brown, Peter J.; Sternbach, Daniel D.; Henke, Brad R.Journal of Medicinal Chemistry (2000), 43 (4), 527-550CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review with 326 refs. is given on peroxisome proliferator-activated receptors (PPARs). The structural and functional anal. of the different PPAR subtypes is summarized and their function as hormone receptors for dietary fatty acids and certain eicosanoids in different species and in many metabolically active tissues is described. Progress is reported in the development of drugs, which use PPARs as mol. targets, for the treatment of human metabolic diseases.
- 117Pollinger, J.; Gellrich, L.; Schierle, S.; Kilu, W.; Schmidt, J.; Kalinowsky, L.; Ohrndorf, J.; Kaiser, A.; Heering, J.; Proschak, E.; Merk, D. Tuning Nuclear Receptor Selectivity of Wy14,643 towards Selective Retinoid X Receptor Modulation. J. Med. Chem. 2019, 62 (4), 2112– 2126, DOI: 10.1021/acs.jmedchem.8b01848[ACS Full Text], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlCgs78%253D&md5=627619c57f03ff4d0223c791154a9cffTuning nuclear receptor selectivity of Wy14,643 towards selective retinoid X receptor modulationPollinger, Julius; Gellrich, Leonie; Schierle, Simone; Kilu, Whitney; Schmidt, Jurema; Kalinowsky, Lena; Ohrndorf, Julia; Kaiser, Astrid; Heering, Jan; Proschak, Ewgenij; Merk, DanielJournal of Medicinal Chemistry (2019), 62 (4), 2112-2126CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 (I) in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compd. as an RXR agonist explaining the pleiotropic effects and report its systematic structure-activity relationship anal. with the discovery of specific mol. determinants driving activity on PPARs and RXRs. We have designed close analogs of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacol. tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist (II) revealed activity in vivo and active concns. in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery.
- 118Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.; Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.; Kliewer, S. A.; Lehmann, J. M. The Structure-Activity Relationship between Peroxisome Proliferator-Activated Receptor γ Agonism and the Antihyperglycemic Activity of Thiazolidinediones. J. Med. Chem. 1996, 39 (3), 665– 668, DOI: 10.1021/jm950395a[ACS Full Text], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xjt1Ortw%253D%253D&md5=cc73c6a8157b6ea258b2f6b3deb6c817The Structure-Activity Relationship between Peroxisome Proliferator-Activated Receptor γ Agonism and the Anti-Hyperglycemic Activity of ThiazolidinedionesWillson, Timothy M.; Cobb, Jeffrey E.; Cowan, David J.; Wiethe, Robert W.; Correa, Itzela D.; Prakash, Shimoga R.; Beck, Kelli D.; Moore, Linda B.; Kliewer, Steven A.; Lehmann, Juergen M.Journal of Medicinal Chemistry (1996), 39 (3), 665-8CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of thiazolidinediones and related compds. with known antidiabetic activity were tested for their in vitro activity on the peroxisome proliferator-activated receptor γ (PPARγ). A correlation between the PPARγ agonist activity and the in vivo antihyperglycemic potency in ob/ob mice was obsd. These results suggest that PPARγ is the mol. target for the antidiabetic activity of the thiazolidinediones.
- 119Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A. An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-Activated Receptor γ (PPARγ). J. Biol. Chem. 1995, 270 (22), 12953– 12956, DOI: 10.1074/jbc.270.22.12953[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmtV2itr0%253D&md5=c32a81ccaaa72abfb879238802640b4dAn antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ)Lehmann, Juergen M.; Moore, Linda B.; Simth-Oliver, Tracey A.; Wilkison, William O.; Willson, Timothy M.; Kliewer, Steven A.Journal of Biological Chemistry (1995), 270 (22), 12953-6CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Thiazolidinedione derivs. are antidiabetic agents that increase the insulin sensitivity of target tissues in animal models of non-insulin-dependent diabetes mellitus. In vitro, thiazolidinediones promote adipocyte differentiation of preadipocyte and mesenchymal stem cell lines; however, the mol. basis for this adipogenic effect has remained unclear. Here, the authors report that thiazolidinediones are potent and selective activators of peroxisome proliferator-activated receptor γ(PPARγ), a member of the nuclear receptor superfamily recently shown to function in adipogenesis. The most potent of these agents, BRL49653, binds to PPARγ with a Kd of approx. 40 nM. Treatment of pluripotent C3H10T1/2 stem cells with BRL49653 results in efficient differentiation to adipocytes. These data are the first demonstration of a high affinity PPAR ligand and provide strong evidence that PPARγ is a mol. target for the adipogenic effects of thiazolidinediones. Furthermore, these data raise the intriguing possibility that PPARγ is a target for the therapeutic actions of this class of compds.
- 120Brown, K. K.; Henke, B. R.; Blanchard, S. G.; Cobb, J. E.; Mook, R.; Kaldor, I.; Kliewer, S. A.; Lehmann, J. M.; Lenhard, J. M.; Harrington, W. W.; Novak, P. J.; Faison, W.; Binz, J. G.; Hashim, M. A.; Oliver, W. O.; Brown, H. R.; Parks, D. J.; Plunket, K. D.; Tong, W. Q.; Menius, J. A.; Adkison, K.; Noble, S. A.; Willson, T. M. A Novel N-Aryl Tyrosine Activator of Peroxisome Proliferator-Activated Receptor-γ Reverses the Diabetic Phenotype of the Zucker Diabetic Fatty Rat. Diabetes 1999, 48 (7), 1415– 1424, DOI: 10.2337/diabetes.48.7.1415[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXktFantbc%253D&md5=2a9d1c260d352ba195efbc6006a30b2bA novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-γ reverses the diabetic phenotype of the Zucker diabetic fatty ratBrown, Kathleen K.; Henke, Brad R.; Blanchard, Steven G.; Cobb, Jeff E.; Mook, Robert; Kaldor, Istvan; Kliewer, Steven A.; Lehmann, Jurgen M.; Lenhard, James M.; Harrington, Wallace W.; Novak, Paul J.; Faison, Walter; Binz, Jane G.; Hashim, Mir A.; Oliver, William O.; Brown, H. Roger; Parks, Derek J.; Plunket, Kelli D.; Tong, Wei-Qin; Menius, J. Alan; Adkison, Kimberly; Noble, Stewart A.; Willson, Timothy M.Diabetes (1999), 48 (7), 1415-1424CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association)The discovery that peroxisome proliferator-activated receptor (PPAR)-γ was the mol. target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-γ in the regulation of carbohydrate and lipid metab. Through the use of high-through-put biochem. assays, GW1929, a novel N-aryl tyrosine activator of human PPAR-γ, was identified. Chronic oral administration of GW1929 or troglitazone to Zucker diabetic fatty (ZDF) rats resulted in dose-dependent decreases in daily glucose, free fatty acid, and triglyceride exposure compared with pretreatment values, as well as significant decreases in glycosylated Hb. Whole body insulin sensitivity, as detd. by the euglycemic-hyperinsulinemic clamp technique, was significantly increased in treated animals. Comparison of the magnitude of glucose lowering as a function of serum drug concns. showed that GW1929 was 2 orders of magnitude more potent than troglitazone in vivo. These data were consistent with the relative in vitro potencies of GW1929 and troglitazone. Isolated perfused pancreas studies performed at the end of the study confirmed that pancreata from vehicle-treated rats showed no increase in insulin secretion in response to a step change in glucose from 3 to 10 mmol/l. In contrast, pancreata from animals treated with GW1929 showed a first- and second-phase insulin secretion pattern. Consistent with the functional data from the perfusion expts., animals treated with the PPAR-γ agonist had more normal islet architecture with preserved insulin staining compared with vehicle-treated ZDF rats. This is the first demonstration of in vivo efficacy of a novel nonthiazolidine-dione identified as a high-affinity ligand for human PPAR-γ. The increased potency of GW1929 compared with troglitazone both in vitro and in vivo may translate into improved clin. efficacy when used as monotherapy in type 2 diabetic patients. In addn., the significant improvement in daily meal tolerance may impact cardiovascular risk factor management in these patients.
- 121Hanke, T.; Cheung, S.-Y.; Kilu, W.; Heering, J.; Ni, X.; Planz, V.; Schierle, S.; Faudone, G.; Friedrich, M.; Wanior, M.; Werz, O.; Windbergs, M.; Proschak, E.; Schubert-Zsilavecz, M.; Chaikuad, A.; Knapp, S.; Merk, D. A Selective Modulator of Peroxisome Proliferator-Activated Receptor γ with an Unprecedented Binding Mode. J. Med. Chem. 2020, 63 (9), 4555– 4561, DOI: 10.1021/acs.jmedchem.9b01786[ACS Full Text], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsl2is7g%253D&md5=7cab05991f3a96acd2c68d3d960685e3A Selective Modulator of Peroxisome Proliferator-Activated Receptor γ with an Unprecedented Binding ModeHanke, Thomas; Cheung, Sun-Yee; Kilu, Whitney; Heering, Jan; Ni, Xiaomin; Planz, Viktoria; Schierle, Simone; Faudone, Giuseppe; Friedrich, Marius; Wanior, Marek; Werz, Oliver; Windbergs, Maike; Proschak, Ewgenij; Schubert-Zsilavecz, Manfred; Chaikuad, Apirat; Knapp, Stefan; Merk, DanielJournal of Medicinal Chemistry (2020), 63 (9), 4555-4561CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The nuclear peroxisome proliferator-activated receptor γ has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also assocd. with marked adverse effects and novel modes of PPARγ modulation are required. Here, we report the discovery and profiling of a new PPARγ modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARγ ligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPARγ activation with a high eudysmic ratio. The new PPARγ modulator revealed outstanding selectivity over the PPARα and PPARδ subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.
- 122Leesnitzer, L. M.; Parks, D. J.; Bledsoe, R. K.; Cobb, J. E.; Collins, J. L.; Consler, T. G.; Davis, R. G.; Hull-Ryde, E. A.; Lenhard, J. M.; Patel, L.; Plunket, K. D.; Shenk, J. L.; Stimmel, J. B.; Therapontos, C.; Willson, T. M.; Blanchard, S. G. Functional Consequences of Cysteine Modification in the Ligand Binding Sites of Peroxisome Proliferator Activated Receptors by GW9662. Biochemistry 2002, 41 (21), 6640– 6650, DOI: 10.1021/bi0159581[ACS Full Text], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtF2htLo%253D&md5=4c8b3355a3a3b43577749d7805f85affFunctional Consequences of Cysteine Modification in the Ligand Binding Sites of Peroxisome Proliferator Activated Receptors by GW9662Leesnitzer, Lisa M.; Parks, Derek J.; Bledsoe, Randy K.; Cobb, Jeff E.; Collins, Jon L.; Consler, Thomas G.; Davis, Roderick G.; Hull-Ryde, Emily A.; Lenhard, James M.; Patel, Lisa; Plunket, Kelli D.; Shenk, Jennifer L.; Stimmel, Julie B.; Therapontos, Christina; Willson, Timothy M.; Blanchard, Steven G.Biochemistry (2002), 41 (21), 6640-6650CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)In the course of a high throughput screen to search for ligands of peroxisome proliferator activated receptor-γ (PPARγ), the authors identified GW9662 using a competition binding assay against the human ligand binding domain. GW9662 had nanomolar IC50 vs. PPARγ and was 10- and 600-fold less potent in binding expts. using PPARα and PPARδ, resp. Pretreatment of all three PPARs with GW9662 resulted in the irreversible loss of ligand binding as assessed by scintillation proximity assay. Incubation of PPAR with GW9662 resulted in a change in the absorbance spectra of the receptors consistent with covalent modification. Mass spectrometric anal. of the PPARγ ligand binding domain treated with GW9662 established Cys285 as the site of covalent modification. This cysteine is conserved among all three PPARs. In cell-based reporter assays, GW9662 was a potent and selective antagonist of full-length PPARγ. The functional activity of GW9662 as an antagonist of PPARγ was confirmed in an assay of adipocyte differentiation. GW9662 showed essentially no effect on transcription when tested using both full-length PPARδ and PPARα. Time-resolved fluorescence assays of ligand-modulated receptor heterodimerization, coactivator binding, and corepressor binding were consistent with the effects obsd. in the reporter gene assays. Control activators increased PPAR: RXR heterodimer formation and coactivator binding to both PPARγ and PPARδ. Corepressor binding was decreased. In the case of PPARα, GW9662 treatment did not significantly increase heterodimerization and coactivator binding or decrease corepressor binding. The exptl. data indicate that GW9662 modification of each of the three PPARs results in different functional consequences. The selective and irreversible nature of GW9662 treatment, and the observation that activity is maintained in cell culture expts., suggests that this compd. may be a useful tool for elucidation of the role of PPARγ in biol. processes.
- 123Oliver, W. R.; Shenk, J. L.; Snaith, M. R.; Russell, C. S.; Plunket, K. D.; Bodkin, N. L.; Lewis, M. C.; Winegar, D. A.; Sznaidman, M. L.; Lambert, M. H.; Xu, H. E.; Sternbach, D. D.; Kliewer, S. A.; Hansen, B. C.; Willson, T. M. A Selective Peroxisome Proliferator-Activated Receptor δ Agonist Promotes Reverse Cholesterol Transport. Proc. Natl. Acad. Sci. U. S. A. 2001, 98 (9), 5306– 5311, DOI: 10.1073/pnas.091021198[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjt1Ontro%253D&md5=a831ae5815399dad336dd50e852ed3f8A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transportOliver, William R., Jr.; Shenk, Jennifer L.; Snaith, Mike R.; Russell, Caroline S.; Plunket, Kelli D.; Bodkin, Noni L.; Lewis, Michael C.; Winegar, Deborah A.; Sznaidman, Marcos L.; Lambert, Millard H.; Xu, H. Eric; Sternbach, Daniel D.; Kliewer, Steven A.; Hansen, Barbara C.; Willson, Timothy M.Proceedings of the National Academy of Sciences of the United States of America (2001), 98 (9), 5306-5311CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metab. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the α (NR1C1) and γ (NR1C3) subtypes, resp. By contrast, the therapeutic potential of the δ (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chem. and structure-based drug design to develop a potent and subtype-selective PPARδ agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high d. lipoprotein cholesterol while lowering the levels of small-dense low d. lipoprotein, fasting triglycerides, and fasting insulin. Our results suggest that PPARδ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease assocd. with the metabolic syndrome X.
- 124Sznaidman, M. L.; Haffner, C. D.; Maloney, P. R.; Fivush, A.; Chao, E.; Goreham, D.; Sierra, M. L.; LeGrumelec, C.; Xu, H. E.; Montana, V. G.; Lambert, M. H.; Willson, T. M.; Oliver, W. R.; Sternbach, D. D. Novel Selective Small Molecule Agonists for Peroxisome Proliferator-Activated Receptor δ (PPARδ) - Synthesis and Biological Activity. Bioorg. Med. Chem. Lett. 2003, 13 (9), 1517– 1521, DOI: 10.1016/S0960-894X(03)00207-5[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXivFemu70%253D&md5=9d0d967f6652b200ba3610657b7676b7Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ) - synthesis and biological activitySznaidman, Marcos L.; Haffner, Curt D.; Maloney, Patrick R.; Fivush, Adam; Chao, Esther; Goreham, Donna; Sierra, Michael L.; LeGrumelec, Christelle; Xu, H. Eric; Montana, Valerie G.; Lambert, Millard H.; Willson, Timothy M.; Oliver, William R.; Sternbach, Daniel D.Bioorganic & Medicinal Chemistry Letters (2003), 13 (9), 1517-1521CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)The authors report the synthesis and biol. activity of a new series of small mol. agonists of the human Peroxisome Proliferator-Activated Receptor δ (PPARδ). Several hits were identified from original libraries contg. lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to two compds. (GW501516 and GW0742) which show an EC50 of 1.1 nM against PPARδ with 1000-fold selectivity over the other human subtypes.
- 125Zhang, R.; Wang, A.; DeAngelis, A.; Pelton, P.; Xu, J.; Zhu, P.; Zhou, L.; Demarest, K.; Murray, W. V.; Kuo, G.-H. Discovery of Para-Alkylthiophenoxyacetic Acids as a Novel Series of Potent and Selective PPARδ Agonists. Bioorg. Med. Chem. Lett. 2007, 17 (14), 3855– 3859, DOI: 10.1016/j.bmcl.2007.05.007[Crossref], [PubMed], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmvVCltbw%253D&md5=b7974387d421bb4f1fa6882ab89733dfDiscovery of para-alkylthiophenoxyacetic acids as a novel series of potent and selective PPARδ agonistsZhang, Rui; Wang, Aihua; DeAngelis, Alan; Pelton, Patricia; Xu, Jun; Zhu, Peifang; Zhou, Lubing; Demarest, Keith; Murray, William V.; Kuo, Gee-HongBioorganic & Medicinal Chemistry Letters (2007), 17 (14), 3855-3859CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)A novel series of potent and selective PPARδ agonists, p-alkylthiophenoxyacetic acids [I, X = S, O, S(O); Y = O, CH2; R = OH, MeO, OMOM, Me, etc.] was identified. The synthesis and structure-activity relationships are described.
- 126Chang, K. L.; Pee, H. N.; Yang, S.; Ho, P. C. Influence of Drug Transporters and Stereoselectivity on the Brain Penetration of Pioglitazone as a Potential Medicine against Alzheimer’s Disease. Sci. Rep. 2015, 5, 9000, DOI: 10.1038/srep09000[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosVKmtb4%253D&md5=9cfe2009ffcd0aa4bea3c887d8dcada5Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer's diseaseChang, Kai Lun; Pee, Hai Ning; Yang, Shili; Ho, Paul C.Scientific Reports (2015), 5 (), 9000CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Pioglitazone is currently undergoing clin. trials for treatment of Alzheimer's disease (AD). However, poor brain penetration remains an obstacle to development of the drug for such intended clin. uses. In this study, we demonstrate that the inhibition of P-glycoprotein (P-gp) significantly increases brain penetration of pioglitazone, whereas inhibition of breast cancer resistance protein (BCRP) has little effect. We also investigate the stereoselectivity of pioglitazone uptake in the brain. When mice were dosed with racemic pioglitazone, the concn. of (+)-pioglitazone was 46.6% higher than that of (-)-pioglitazone in brain tissue and 67.7% lower than that of (-)-pioglitazone in plasma. Dosing mice with pure (+)-pioglitazone led to a 76% increase in brain exposure levels compared to those from an equiv. dose of racemic pioglitazone. Pure (+)-pioglitazone was also shown to have comparable amyloid-lowering capabilities to the racemic pioglitazone in an in vitro AD model. These results suggest that P-gp may act as a stereoselective barrier to prevent pioglitazone entry into the brain. Dosing with (+)-pioglitazone instead of the racemic mixt. may result in higher levels of brain exposure to pioglitazone, thus potentially improving the development of pioglitazone treatment of AD.
- 127Sime, M.; Allan, A. C.; Chapman, P.; Fieldhouse, C.; Giblin, G. M. P.; Healy, M. P.; Lambert, M. H.; Leesnitzer, L. M.; Lewis, A.; Merrihew, R. V.; Rutter, R. A.; Sasse, R.; Shearer, B. G.; Willson, T. M.; Xu, R. X.; Virley, D. J. Discovery of GSK1997132B a Novel Centrally Penetrant Benzimidazole PPARγ Partial Agonist. Bioorg. Med. Chem. Lett. 2011, 21 (18), 5568– 5572, DOI: 10.1016/j.bmcl.2011.06.088[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVKisL3M&md5=7f93f4621adf179a2ff97a2be9849bbbDiscovery of GSK1997132B a novel centrally penetrant benzimidazole PPARγ partial agonistSime, Mairi; Allan, Amanda C.; Chapman, Paul; Fieldhouse, Charlotte; Giblin, Gerard M. P.; Healy, Mark P.; Lambert, Millard H.; Leesnitzer, Lisa M.; Lewis, Ann; Merrihew, Raymond V.; Rutter, Richard A.; Sasse, Rosemary; Shearer, Barry G.; Willson, Timothy M.; Xu, Robert X.; Virley, David J.Bioorganic & Medicinal Chemistry Letters (2011), 21 (18), 5568-5572CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metab., glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B (I) a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.
- 128Uriz-Huarte, A.; Date, A.; Ang, H.; Ali, S.; Brady, H. J. M.; Fuchter, M. J. The Transcriptional Repressor REV-ERB as a Novel Target for Disease. Bioorg. Med. Chem. Lett. 2020, 30 (17), 127395, DOI: 10.1016/j.bmcl.2020.127395[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVWhs7fP&md5=bba3790573dd756a54af723c25224adeThe transcriptional repressor REV-ERB as a novel target for diseaseUriz-Huarte, Amaia; Date, Amrita; Ang, Heather; Ali, Simak; Brady, Hugh J. M.; Fuchter, Matthew J.Bioorganic & Medicinal Chemistry Letters (2020), 30 (17), 127395CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. REV-ERB is a member of the nuclear receptor superfamily of transcription factors involved in the regulation of many physiol. processes, from circadian rhythm, to immune function and metab. Accordingly, REV-ERB has been considered as a promising, but difficult drug target for the treatment of numerous diseases. Here, we concisely review current understanding of the function of REV-ERB, modulation by endogenous factors and synthetic ligands, and the involvement of REV-ERB in select human diseases. Particular focus is placed on the medicinal chem. of synthetic REV-ERB ligands, which demonstrates the need for higher quality ligands to aid in robust validation of this exciting target.
- 129Kojetin, D. J.; Burris, T. P. REV-ERB and ROR Nuclear Receptors as Drug Targets. Nat. Rev. Drug Discovery 2014, 13 (3), 197– 216, DOI: 10.1038/nrd4100[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjt12hsL0%253D&md5=156f56d5766fec38440a3c0f2e9c753eREV-ERB and ROR nuclear receptors as drug targetsKojetin, Douglas J.; Burris, Thomas P.Nature Reviews Drug Discovery (2014), 13 (3), 197-216CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. The nuclear receptors REV-ERB (consisting of REV-ERBα and REV-ERBβ) and retinoic acid receptor-related orphan receptors (RORs; consisting of RORα, RORβ and RORγ) are involved in many physiol. processes, including regulation of metab., development and immunity as well as the circadian rhythm. The recent characterization of endogenous ligands for these former orphan nuclear receptors has stimulated the development of synthetic ligands and opened up the possibility of targeting these receptors to treat several diseases, including diabetes, atherosclerosis, autoimmunity and cancer. This Review focuses on the latest developments in ROR and REV-ERB pharmacol. indicating that these nuclear receptors are druggable targets and that ligands targeting these receptors may be useful in the treatment of several disorders.
- 130Chang, C.; Loo, C.-S.; Zhao, X.; Solt, L. A.; Liang, Y.; Bapat, S. P.; Cho, H.; Kamenecka, T. M.; Leblanc, M.; Atkins, A. R.; Yu, R. T.; Downes, M.; Burris, T. P.; Evans, R. M.; Zheng, Y. The Nuclear Receptor REV-ERBα Modulates Th17 Cell-Mediated Autoimmune Disease. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (37), 18528– 18536, DOI: 10.1073/pnas.1907563116[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslOhsbnF&md5=1409f2e46939feeb39805270b5312545The nuclear receptor REV-ERBα modulates Th17 cell-mediated autoimmune diseaseChang, Christina; Loo, Chin-San; Zhao, Xuan; Solt, Laura A.; Liang, Yuqiong; Bapat, Sagar P.; Cho, Han; Kamenecka, Theodore M.; Leblanc, Mathias; Atkins, Annette R.; Yu, Ruth T.; Downes, Michael; Burris, Thomas P.; Evans, Ronald M.; Zheng, YeProceedings of the National Academy of Sciences of the United States of America (2019), 116 (37), 18528-18536CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)T helper 17 (Th17) cells produce interleukin-17 (IL-17) cytokines and drive inflammatory responses in autoimmune diseases such as multiple sclerosis. The differentiation of Th17 cells is dependent on the retinoic acid receptor-related orphan nuclear receptor RORγt. Here, we identify REV-ERBα (encoded by Nr1d1), a member of the nuclear hormone receptor family, as a transcriptional repressor that antagonizes RORγt function in Th17 cells. REV-ERBα binds to ROR response elements (RORE) in Th17 cells and inhibits the expression of RORγt-dependent genes including Il17a and Il17f. Furthermore, elevated REV-ERBα expression or treatment with a synthetic REV-ERB agonist significantly delays the onset and impedes the progression of exptl. autoimmune encephalomyelitis (EAE). These results suggest that modulating REV-ERBα activity may be used to manipulate Th17 cells in autoimmune diseases.
- 131Lazar, M. A.; Hodin, R. A.; Darling, D. S.; Chin, W. W. A Novel Member of the Thyroid/Steroid Hormone Receptor Family Is Encoded by the Opposite Strand of the Rat c-ErbA Alpha Transcriptional Unit. Mol. Cell. Biol. 1989, 9 (3), 1128– 1136, DOI: 10.1128/MCB.9.3.1128[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXhs1Wn&md5=41918d675e93b04c84aa4f0288af9232A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbAα transcriptional unitLazar, Mitchell A.; Hodin, Richard A.; Darling, Douglas S.; Chin, William W.Molecular and Cellular Biology (1989), 9 (3), 1128-36CODEN: MCEBD4; ISSN:0270-7306.A cDNA encoding a novel member of the thyroid/steroid hormone receptor superfamily, called Rev-ErbAα, was isolated from a rat GH3 cell library. Rev-ErbAα is an ∼56-kilodalton protein most similar in structure to the thyroid hormone receptor (c-erbA) and the retinoic acid receptor, but it does not bind either thyroid hormone or retinoic acid. The mRNA encoding Rev-ErbAα is present in many tissues and is particularly abundant in skeletal muscle and brown fat. A genomic DNA fragment contg. the entire Rev-ErbAα cDNA sequence was isolated and characterized. Remarkably, this DNA fragment also contained a portion of the c-erbAα gene. The r-erbAα-1 and r-erbAα-2 are alternative splice products of the c-erbAα gene and are members of the receptor superfamily. The genes encoding Rev-ErbAα and r-erbAα-2 overlap, with their coding strands oriented opposite one another. A 269-base-pair segment of the bidirectionally transcribed region is exonic in both the Rev-ErbAα and r-erbAα-2 genes, resulting in complementary mRNAs. Thus, through alternative splicing and opposite-strand transcription, a single genomic locus codes for three different members of the thyroid/steroid hormone receptor superfamily. Potential implications of this unusual genomic arrangement are discussed.
- 132Forman, B. M.; Chen, J.; Blumberg, B.; Kliewer, S. A.; Henshaw, R.; Ong, E. S.; Evans, R. M. Cross-Talk among ROR Alpha 1 and the Rev-Erb Family of Orphan Nuclear Receptors. Mol. Endocrinol. 1994, 8 (9), 1253– 1261, DOI: 10.1210/mend.8.9.7838158[Crossref], [PubMed], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmslemsLo%253D&md5=00c997fe0b6796f17e750611d590632dCross-talk among RORα1 and the Rev-erb family of orphan nuclear receptorsForman, Barry Marc; Chen, Jasmine; Blumberg, Bruce; Kliewer, Steven A.; Henshaw, Robert; Ong, Estelita S.; Evans, Ronald M.Molecular Endocrinology (1994), 8 (9), 1253-61CODEN: MOENEN; ISSN:0888-8809.We have cloned Rev-erbβ, a novel isoform of the Rev-erbα orphan nuclear receptor. The DNA binding domains of Rev-erbα and β are highly related to each other and to the retinoic acid related orphan receptor (ROR)/RZR subfamily of nuclear receptors. Indeed, we find that all three receptors bind as monomers to the sequence AATGT-AGGTCA. Whereas RORαf1 constitutively activates transcription through this sequence, both isoforms of Reverb are inactive. When coexpressed, both Rev-erb isoforms suppress the transcriptional activity of RORα1. Our data define Rev-erb and ROR/RZR as a family of related receptors with opposing activities on overlapping regulatory networks.
- 133Dumas, B.; Harding, H. P.; Choi, H. S.; Lehmann, K. A.; Chung, M.; Lazar, M. A.; Moore, D. D. A New Orphan Member of the Nuclear Hormone Receptor Superfamily Closely Related to Rev-Erb. Mol. Endocrinol. 1994, 8 (8), 996– 1005, DOI: 10.1210/mend.8.8.7997240[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXlslSksbk%253D&md5=d0fcc97317dd13640d2acf7effa67028A new orphan member of the nuclear hormone receptor superfamily closely related to Rev-ErbDumas, Bruno; Harding, Heather P.; Choi, Hueng-Sik; Lehmann, Katrina A.; Chung, Mirra; Lazar, Mitchell A.; Moore, David D.Molecular Endocrinology (1994), 8 (8), 996-1005CODEN: MOENEN; ISSN:0888-8809.We have isolated complementary DNA clones encoding a novel orphan member of the nuclear receptor superfamily, termed BD73. This protein shows strong amino acid sequence similarity to the previously described Rev-ErbAα. Unlike Rev-Erb, in which the opposite strand of the C-terminal coding region encodes the C-terminal portion of a variant thyroid hormone receptor isoform, the opposite strand of the C-terminal coding region of BD73 does not have any extensive open reading frames. BD73 mRNA levels are strongly induced by planar arom. antioxidants. Like Rev-Erb, BD73 binds as a monomer to a DNA sequence which consists of a specific A/T-rich sequence upstream of the consensus hexameric half-site specified by the P box of the DNA-binding domain. Amino acid sequence comparisons suggest that the A box sequence, which has been suggested to mediate monomer binding by other superfamily members, lies closer to the DNA-binding domain in BD73 and Rev-Erb than in other receptors. Under the conditions examd., neither BD73 nor Rev-Erb activated reporters contg. multiple copies of their common binding site. Thus, these two orphans may require an as yet unidentified ligand or other signal for such activation. Together, BD73 and Rev-Erb define a subgroup of orphan receptors that bind as monomers to a half-site flanked by a specific and extended A/T-rich sequence.
- 134Yin, L.; Lazar, M. A. The Orphan Nuclear Receptor Rev-Erbα Recruits the N-CoR/Histone Deacetylase 3 Corepressor to Regulate the Circadian Bmal1 Gene. Mol. Endocrinol. 2005, 19 (6), 1452– 1459, DOI: 10.1210/me.2005-0057[Crossref], [PubMed], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkslyqtro%253D&md5=8a1272733fd5b36d75debb72ba1db1a9The orphan nuclear receptor Rev-erbα recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 geneYin, Lei; Lazar, Mitchell A.Molecular Endocrinology (2005), 19 (6), 1452-1459CODEN: MOENEN; ISSN:0888-8809. (Endocrine Society)Transcriptional regulation plays a fundamental role in controlling circadian oscillation of clock gene expression. The orphan nuclear receptor Rev-erbα has recently been implicated as a major regulator of the circadian clock. Expression of Bmal1, the master regulator of circadian rhythm in mammals, is neg. correlated with Rev-erbα mRNA level, but the mol. mechanism underlying this regulation is largely unknown. Here we show that Rev-erbα dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human. Rev-erbα directly binds to the mouse Bmal1 promoter and recruits the endogenous nuclear receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex, in assocn. with a decrease in histone acetylation. The endogenous N-CoR/HDAC3 complex is also assocd. with the endogenous Bmal1 promoter in human HepG2 liver cells, where a redn. in cellular HDAC3 level markedly increases the expression of Bmal1 mRNA. These data demonstrate a new function for the N-CoR/HDAC3 complex in regulating the expression of genes involved in circadian rhythm by functioning as corepressor for Rev-erbα.
- 135Torra, I. P.; Tsibulsky, V.; Delaunay, F.; Saladin, R.; Laudet, V.; Fruchart, J.-C.; Kosykh, V.; Staels, B. Circadian and Glucocorticoid Regulation of Rev-Erbα Expression in Liver. Endocrinology 2000, 141 (10), 3799– 3806, DOI: 10.1210/endo.141.10.7708[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmvVGmsbc%253D&md5=9554cf7fff2be9ac83718c9c94bd844eCircadian and glucocorticoid regulation of Rev-erbα expression in liverTorra, Ines Pineda; Tsibulsky, Vladimir; Delaunay, Franck; Saladin, Regis; Laudet, Vincent; Fruchart, Jean-Charles; Kosykh, Vladimir; Staels, BartEndocrinology (2000), 141 (10), 3799-3806CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)Rev-erbα [NR1D1], a member of the nuclear receptor superfamily, is an orphan receptor that constitutively represses gene transcription. Rev-erbα has been shown to play a role in myocyte differentiation and to be induced during adipogenesis. Furthermore, Rev-erbα is a regulator of lipoprotein metab. It was recently shown that Rev-erbα mRNA levels oscillate diurnally in rat liver. Here, the authors report that the circadian rhythm of Rev-erbα in liver is maintained in primary cultures of rat hepatocytes. Because glucocorticoids have been shown to regulate other transcription factors with circadian expression, it was furthermore examd. whether hepatic Rev-erbα expression is also regulated by glucocorticoids. Treatment of rats with dexamethasone resulted in a decrease of Rev-erbα mRNA levels by 70% after 6 h. Furthermore, dexamethasone decreased Rev-erbα expression in rat primary hepatocytes in a dose-dependent fashion. This effect was mediated by the glucocorticoid receptor because simultaneous addn. of the glucocorticoid antagonist RU486 prevented the decrease in Rev-erbα mRNA levels by dexamethasone. Protein synthesis inhibition with cycloheximide markedly induced Rev-erbα mRNA levels; however, this induction was reduced by dexamethasone supplementation in both rat and human primary hepatocytes. Treatment with actinomycin D blocked the repression of Rev-erbα expression by dexamethasone in rat hepatocytes, suggesting that glucocorticoids regulate Rev-erbα expression at the transcriptional level. Transient transfection expts. further indicated that Rev-erbα promoter activity is repressed by dexamethasone in the presence of cotransfected glucocorticoid receptor. Taken together, these data demonstrate that Rev-erbα expression is under the control of both the circadian clock and glucocorticoids in the liver.
- 136Balsalobre, A.; Damiola, F.; Schibler, U. A Serum Shock Induces Circadian Gene Expression in Mammalian Tissue Culture Cells. Cell 1998, 93 (6), 929– 937, DOI: 10.1016/S0092-8674(00)81199-X[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjvFKqsL8%253D&md5=989e59d9fb65ffa90a7f2700dcc19804A serum shock induces circadian gene expression in mammalian tissue culture cellsBalsalobre, Aurelio; Damiola, Francesca; Schibler, UeliCell (Cambridge, Massachusetts) (1998), 93 (6), 929-937CODEN: CELLB5; ISSN:0092-8674. (Cell Press)The treatment of cultured rat-1 fibroblasts or H35 hepatoma cells with high concns. of serum induces the circadian expression of various genes whose transcription also oscillates in living animals. Oscillating genes include rper1 and rper2 (rat homologs of the Drosophila clock gene period), and the genes encoding the transcription factors Rev-Erbα, DBP, and TEF. In rat-1 fibroblasts, up to three consecutive daily oscillations with an av. period length of 22.5 h could be recorded. The temporal sequence of the various mRNA accumulation cycles is the same in cultured cells and in vivo. The serum shock of rat-1 fibroblasts also results in a transient stimulation of c-fos and rper expression and thus mimics light-induced immediate-early gene expression in the suprachiasmatic nucleus.
- 137Wolff, S. E. C.; Wang, X.-L.; Jiao, H.; Sun, J.; Kalsbeek, A.; Yi, C.-X.; Gao, Y. The Effect of Rev-Erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia. Front. Immunol. 2020, 11, 550145, DOI: 10.3389/fimmu.2020.550145[Crossref], [PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1aktbrP&md5=d45e74ce639254e0c585dfb59d4bb841The Effect of Rev-erba agonist SR9011 on the immune response and cell metabolism of microgliaWolff, Samantha E. C.; Wang, Xiao-Lan; Jiao, Han; Sun, Jia; Kalsbeek, Andries; Yi, Chun-Xia; Gao, YuanqingFrontiers in Immunology (2020), 11 (), 550145CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)Microglia are the immune cells of the brain. Hyperactivation of microglia contributes to the pathol. of metabolic and neuroinflammatory diseases. Evidence has emerged that links the circadian clock, cellular metab., and immune activity in microglia. Rev-erb nuclear receptors are known for their regulatory role in both the mol. clock and cell metab., and have recently been found to play an important role in neuroinflammation. The Rev-erb αagonist SR9011 disrupts circadian rhythm by altering intracellular clock machinery. However, the exact role of Rev-erb αin microglial immunometabolism remains to be elucidated. In the current study, we explored whether SR9011 also had such a detrimental impact on microglial immunometabolic functions. Primary microglia were isolated from 1-3 days old Sprague-Dawley rat pups. The expression of clock genes, cytokines and metabolic genes was evaluated using RT-PCR and rhythmic expression was analyzed. Phagocytic activity was detd. by the uptake capacity of fluorescent microspheres. Mitochondria function was evaluated by measuring oxygen consumption rate and extracellular acidification rate. We found that key cytokines and metabolic genes are rhythmically expressed in microglia. SR9011 disturbed rhythmic expression of clock genes in microglia. Pro-inflammatory cytokine expression was attenuated by SR9011 during an immune challenge by TNF α, while expression of the anti-inflammatory cytokine Il10 was stimulated. Moreover, SR9011 decreased phagocytic activity, mitochondrial respiration, ATP prodn., and metabolic gene expression. Our study highlights the link between the intrinsic clock and immunometabolism of microglia. We show that Rev-erb α is implicated in both metabolic homeostasis and the inflammatory responses in microglia, which has important implications for the treatment of metabolic and neuroinflammatory diseases.
- 138Guo, D.; Zhu, Y.; Sun, H.; Xu, X.; Zhang, S.; Hao, Z.; Wang, G.; Mu, C.; Ren, H. Pharmacological Activation of REV-ERBα Represses LPS-Induced Microglial Activation through the NF-KB Pathway. Acta Pharmacol. Sin. 2019, 40 (1), 26– 34, DOI: 10.1038/s41401-018-0064-0[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVOnu7nN&md5=7a60e0feb50dbf9bed8d441df67e2c8bPharmacological activation of REV-ERBa represses LPS-induced microglial activation through the NF-kB pathwayGuo, Dong-kai; Zhu, Yao; Sun, Hong-yang; Xu, Xing-yun; Zhang, Shun; Hao, Zong-bing; Wang, Guang-hui; Mu, Chen-chen; Ren, Hai-gangActa Pharmacologica Sinica (2019), 40 (1), 26-34CODEN: APSCG5; ISSN:1671-4083. (Nature Research)Microglia-mediated neuroinflammation is tightly assocd. with various neurodegenerative diseases and psychiatric disorders. However, the role of REV-ERBa in neuroinflammation is largely unclear. In this study, we investigated whether and how pharmacol. activation of REV-ERBa affected lipopolysaccharide (LPS)-induced neuroinflammation in mouse microglia in vitro and in vivo. In BV2 cells or primary mouse cultured microglia, application of REV-ERBa agonist GSK4112 or SR9011 dose-dependently suppressed LPS-induced microglial activation through the nuclear factor kappa B (NF-kB) pathway. In BV2 cells, pretreatment with GSK4112 inhibited LPS-induced phosphorylation of the inhibitor of NF-kB alpha (IkBa) kinase (IkK), thus restraining the phosphorylation and degrdn. of IkBa, and blocked the nuclear translocation of p65, a NF-kB subunit, thereby suppressing the expression and secretion of the proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor a (TNFa). Moreover, REV-ERBa agonist-induced inhibition on neuroinflammation protected neurons from microglial activation-induced damage, which were also demonstrated in mice with their ventral midbrain microinjected with GSK4112, and then stimulated with LPS. Our results reveal that enhanced REV-ERBa activity suppresses microglial activation through the NF-kB pathway in the central nervous system.
- 139Roby, D. A.; Ruiz, F.; Kermath, B. A.; Voorhees, J. R.; Niehoff, M.; Zhang, J.; Morley, J. E.; Musiek, E. S.; Farr, S. A.; Burris, T. P. Pharmacological Activation of the Nuclear Receptor REV-ERB Reverses Cognitive Deficits and Reduces Amyloid-β Burden in a Mouse Model of Alzheimer’s Disease. PLoS One 2019, 14 (4), e0215004, DOI: 10.1371/journal.pone.0215004[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpslWnu7c%253D&md5=6ffeb1c6dd79062fd2e0552b1059cea7Pharmacological activation of the nuclear receptor REV-ERB reverses cognitive deficits and reduces amyloid-β burden in a mouse model of Alzheimer's diseaseRoby, Deborah A.; Ruiz, Fernanda; Kermath, Bailey A.; Voorhees, Jaymie R.; Niehoff, Michael; Zhang, Jinsong; Morley, John E.; Musiek, Erik S.; Farr, Susan A.; Burris, Thomas P.PLoS One (2019), 14 (4), e0215004CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Alzheimer's disease currently lacks treatment options that effectively reverse the biol./anatomical pathol. and cognitive deficits assocd. with the disease. Loss of function of the nuclear receptor REV-ERB is assocd. with reduced cognitive function in mouse models. The effect of enhanced REV-ERB activity on cognitive function has not been examd. In this study, we tested the hypothesis that enhanced REV-ERB function may enhance cognitive function in a model of Alzheimer's disease. We utilized the REV-ERB agonist SR9009 to pharmacol. activate the activity of REV-ERB in the SAMP8 mouse model of Alzheimer's disease. SR9009 reversed cognitive dysfunction of an aged SAMP8 mouse in several behavioral assays including novel object recognition, T-maze foot shock avoidance, and lever press operant conditioning task assessments. SR9009 treatment reduced amyloid-β 1-40 and 1-42 levels in the cortex, which is consistent with improved cognitive function. Furthermore, SR9009 treatment led to increased hippocampal PSD-95, cortical synaptophysin expression and the no. of synapses suggesting improvement in synaptic function. We conclude that REV-ERB is a potential target for treatment of Alzheimer's disease.
- 140Griffin, P.; Dimitry, J. M.; Sheehan, P. W.; Lananna, B. V.; Guo, C.; Robinette, M. L.; Hayes, M. E.; Cedeño, M. R.; Nadarajah, C. J.; Ezerskiy, L. A.; Colonna, M.; Zhang, J.; Bauer, A. Q.; Burris, T. P.; Musiek, E. S. Circadian Clock Protein Rev-Erbα Regulates Neuroinflammation. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (11), 5102– 5107, DOI: 10.1073/pnas.1812405116[Crossref], [PubMed], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkvVCjtbw%253D&md5=abd5ddc720e1bb661f2b932ecbc97a12Circadian clock protein Rev-erbα regulates neuroinflammationGriffin, Percy; Dimitry, Julie M.; Sheehan, Patrick W.; Lananna, Brian V.; Guo, Chun; Robinette, Michelle L.; Hayes, Matthew E.; CedeA±o, Michelle R.; Nadarajah, Collin J.; Ezerskiy, Lubov A.; Colonna, Marco; Zhang, Jinsong; Bauer, Adam Q.; Burris, Thomas P.; Musiek, Erik S.Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (11), 5102-5107CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are assocd. with neuroinflammation. Circadian rhythm dysfunction has been assocd. with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα±, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We obsd. time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα mice. Rev-erbα± deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic anal. of hippocampus from Rev-erbα mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunopptn. revealed that Rev-erbα± phys. interacts with the promoter regions of several NF-κB-related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacol. activation of Rev-erbs with the small mol. agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erb± deletion influenced neuronal health, as conditioned media from Rev-erbα-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that obsd. in neurodegenerative models. Our results reveal Rev-erbα as a pharmacol. accessible link between the circadian clock and neuroinflammation.
- 141Lee, J.; Kim, D. E.; Griffin, P.; Sheehan, P. W.; Kim, D.-H.; Musiek, E. S.; Yoon, S.-Y. Inhibition of REV-ERBs Stimulates Microglial Amyloid-Beta Clearance and Reduces Amyloid Plaque Deposition in the 5XFAD Mouse Model of Alzheimer’s Disease. Aging Cell 2020, 19 (2), e13078, DOI: 10.1111/acel.13078[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1yjtrrN&md5=c318b7b7d2d3efb2a092ae1787bf8de9Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer's diseaseLee, Jiyeon; Kim, Do-Eun; Griffin, Percy; Sheehan, Patrick W.; Kim, Dong-Hou; Musiek, Erik S.; Yoon, Seung-YongAging Cell (2020), 19 (2), e13078CODEN: ACGECQ; ISSN:1474-9718. (Wiley-Blackwell)A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the mol. clock in regulating amyloid-beta (Aβ) pathol. is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ1-42 (fAβ1-42) than at CT12. BMAL1 directly drives transcription of REV-ERB proteins, which are implicated in microglial activation. Interestingly, pharmacol. inhibition of REV-ERBs with the small mol. antagonist SR8278 or genetic knockdown of REV-ERBs-accelerated microglial uptake of fAβ1-42 and increased transcription of BMAL1. SR8278 also promoted microglia polarization toward a phagocytic M2-like phenotype with increased P2Y12 receptor expression. Finally, constitutive deletion of Rev-erba in the 5XFAD model of AD decreased amyloid plaque no. and size and prevented plaque-assocd. increases in disease-assocd. microglia markers including TREM2, CD45, and Clec7a. Altogether, our work suggests a novel strategy for controlling Aβ clearance and neuroinflammation by targeting REV-ERBs and provides new insights into the role of REV-ERBs in AD.
- 142Raghuram, S.; Stayrook, K. R.; Huang, P.; Rogers, P. M.; Nosie, A. K.; McClure, D. B.; Burris, L. L.; Khorasanizadeh, S.; Burris, T. P.; Rastinejad, F. Identification of Heme as the Ligand for the Orphan Nuclear Receptors REV-ERBα and REV-ERBβ. Nat. Struct. Mol. Biol. 2007, 14 (12), 1207– 1213, DOI: 10.1038/nsmb1344[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtl2hu73E&md5=62aabcd486e5edb811d7ea18597ce77aIdentification of heme as the ligand for the orphan nuclear receptors REV-ERBα and REV-ERBβRaghuram, Srilatha; Stayrook, Keith R.; Huang, Pengxiang; Rogers, Pamela M.; Nosie, Amanda K.; McClure, Don B.; Burris, Lorri L.; Khorasanizadeh, Sepideh; Burris, Thomas P.; Rastinejad, FraydoonNature Structural & Molecular Biology (2007), 14 (12), 1207-1213CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)The nuclear receptors REV-ERBα (encoded by NR1D1) and REV-ERBβ (NR1D2) have remained orphans owing to the lack of identified physiol. ligands. Here we show that heme is a physiol. ligand of both receptors. Heme assocs. with the ligand-binding domains of the REV-ERB receptors with a 1:1 stoichiometry and enhances the thermal stability of the proteins. Results from expts. of heme depletion in mammalian cells indicate that heme binding to REV-ERB causes the recruitment of the co-repressor NCoR, leading to repression of target genes including BMAL1 (official symbol ARNTL), an essential component of the circadian oscillator. Heme extends the known types of ligands used by the human nuclear receptor family beyond the endocrine hormones and dietary lipids described so far. Our results further indicate that heme regulation of REV-ERBs may link the control of metab. and the mammalian clock.
- 143Trump, R. P.; Bresciani, S.; Cooper, A. W. J.; Tellam, J. P.; Wojno, J.; Blaikley, J.; Orband-Miller, L. A.; Kashatus, J. A.; Boudjelal, M.; Dawson, H. C.; Loudon, A.; Ray, D.; Grant, D.; Farrow, S. N.; Willson, T. M.; Tomkinson, N. C. O. Optimized Chemical Probes for REV-ERBα. J. Med. Chem. 2013, 56 (11), 4729– 4737, DOI: 10.1021/jm400458q[ACS Full Text], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsVWisr8%253D&md5=cbce9246fa2f76ecfc78bc87d5c40a0fOptimized Chemical Probes for REV-ERBαTrump, Ryan P.; Bresciani, Stefano; Cooper, Anthony W. J.; Tellam, James P.; Wojno, Justyna; Blaikley, John; Orband-Miller, Lisa A.; Kashatus, Jennifer A.; Boudjelal, Mohamed; Dawson, Helen C.; Loudon, Andrew; Ray, David; Grant, Daniel; Farrow, Stuart N.; Willson, Timothy M.; Tomkinson, Nicholas C. O.Journal of Medicinal Chemistry (2013), 56 (11), 4729-4737CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)REV-ERBα has emerged as an important target for regulation of circadian rhythm and its assocd. physiol. Herein, the authors report on the optimization of a series of REV-ERBα agonists based on GSK4112 for potency, selectivity, and bioavailability. Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either i.v. or oral dosing.
- 144Noel, R.; Song, X.; Shin, Y.; Banerjee, S.; Kojetin, D.; Lin, L.; Ruiz, C. H.; Cameron, M. D.; Burris, T. P.; Kamenecka, T. M. Synthesis and SAR of Tetrahydroisoquinolines as Rev-Erbα Agonists. Bioorg. Med. Chem. Lett. 2012, 22 (11), 3739– 3742, DOI: 10.1016/j.bmcl.2012.04.023[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsF2ltb4%253D&md5=87d4951c1b9c2db42a71f0a1522b84d3Synthesis and SAR of tetrahydroisoquinolines as Rev-erbα agonistsNoel, Romain; Song, Xinyi; Shin, Youseung; Banerjee, Subhashis; Kojetin, Douglas; Lin, Li; Ruiz, Claudia H.; Cameron, Michael D.; Burris, Thomas P.; Kamenecka, Theodore M.Bioorganic & Medicinal Chemistry Letters (2012), 22 (11), 3739-3742CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The design and synthesis of a novel series of Rev-erbα agonists is described. The development and optimization of the tetrahydroisoquinoline series was carried out from an earlier acyclic series of Rev-erbα agonists. Through the optimization of the scaffold I, several potent compds. with good in vivo profiles were discovered.
- 145Westermaier, Y.; Ruiz-Carmona, S.; Theret, I.; Perron-Sierra, F.; Poissonnet, G.; Dacquet, C.; Boutin, J. A.; Ducrot, P.; Barril, X. Binding Mode Prediction and MD/MMPBSA-Based Free Energy Ranking for Agonists of REV-ERBα/NCoR. J. Comput.-Aided Mol. Des. 2017, 31 (8), 755– 775, DOI: 10.1007/s10822-017-0040-7[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFOlu73F&md5=0f655bb3cb92851272023caa6e7a93fcBinding mode prediction and MD/MMPBSA-based free energy ranking for agonists of REV-ERBα/NCoRWestermaier, Yvonne; Ruiz-Carmona, Sergio; Theret, Isabelle; Perron-Sierra, Francoise; Poissonnet, Guillaume; Dacquet, Catherine; Boutin, Jean A.; Ducrot, Pierre; Barril, XavierJournal of Computer-Aided Molecular Design (2017), 31 (8), 755-775CODEN: JCADEQ; ISSN:0920-654X. (Springer)The knowledge of the free energy of binding of small mols. to a macromol. target is crucial in drug design as is the ability to predict the functional consequences of binding. We highlight how a mol. dynamics (MD)-based approach can be used to predict the free energy of small mols., and to provide priorities for the synthesis and the validation via in vitro tests. Here, we study the dynamics and energetics of the nuclear receptor REV-ERBα with its co-repressor NCoR and 35 novel agonists. Our in silico approach combines mol. docking, mol. dynamics (MD), solvent-accessible surface area (SASA) and mol. mechanics poisson boltzmann surface area (MMPBSA) calcns. While docking yielded initial hints on the binding modes, their stability was assessed by MD. The SASA calcns. revealed that the presence of the ligand led to a higher exposure of hydrophobic REV-ERB residues for NCoR recruitment. MMPBSA was very successful in ranking ligands by potency in a retrospective and prospective manner. Particularly, the prospective MMPBSA ranking-based validations for four compds., three predicted to be active and one weakly active, were confirmed exptl.
- 146Kojetin, D.; Wang, Y.; Kamenecka, T. M.; Burris, T. P. Identification of SR8278, a Synthetic Antagonist of the Nuclear Heme Receptor REV-ERB. ACS Chem. Biol. 2011, 6 (2), 131– 134, DOI: 10.1021/cb1002575[ACS Full Text], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtl2rs7fI&md5=2de14b79ed592d0062e9e4bc34620892Identification of SR8278, a Synthetic Antagonist of the Nuclear Heme Receptor REV-ERBKojetin, Douglas; Wang, Yongjun; Kamenecka, Theodore M.; Burris, Thomas P.ACS Chemical Biology (2011), 6 (2), 131-134CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)REV-ERBα is a member of the nuclear receptor superfamily that functions as a receptor for the porphoryin heme. REV-ERBα suppresses transcription of its target genes in a heme-dependent manner. Recently, the first nonporphyrin synthetic ligand for REV-ERBα, GSK4112, was designed, and it mimics the action of heme acting as agonist. Here, we report the identification of the first REV-ERB antagonist, SR8278. SR8278 is structurally similar to the agonist but blocks the ability of the GSK4112 to enhance REV-ERBα-dependent repression in a cotransfection assay. Addnl., whereas GSK4112 suppresses the expression of REV-ERBα target genes involved in gluconeogenesis, SR8278 stimulates the expression of these genes. Thus, SR8278 represents a unique chem. tool for probing REV-ERB function and may serve as a point for initiation of further optimization to develop REV-ERB antagonists with the ability to explore circadian and metabolic functions.
- 147De Mei, C; Ercolani, L; Parodi, C; Veronesi, M; Vecchio, C L.; Bottegoni, G; Torrente, E; Scarpelli, R; Marotta, R; Ruffili, R; Mattioli, M; Reggiani, A; Wade, M; Grimaldi, B Dual Inhibition of REV-ERBβ and Autophagy as a Novel Pharmacological Approach to Induce Cytotoxicity in Cancer Cells. Oncogene 2015, 34 (20), 2597– 2608, DOI: 10.1038/onc.2014.203[Crossref], [PubMed], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFGqtr7J&md5=6ae73694ed0eb85a1ab92f28158135e8Dual inhibition of REV-ERBβ and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cellsDe Mei, C.; Ercolani, L.; Parodi, C.; Veronesi, M.; Vecchio, C. Lo; Bottegoni, G.; Torrente, E.; Scarpelli, R.; Marotta, R.; Ruffili, R.; Mattioli, M.; Reggiani, A.; Wade, M.; Grimaldi, B.Oncogene (2015), 34 (20), 2597-2608CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)REV-ERBα and REV-ERBβ nuclear receptors regulate several physiol. processes, including circadian rhythm and metab. A previous study reported the REV-ERBα gene to be co-overexpressed with ERBB2 in breast cancer cell lines. Surprisingly, we found that several tumor types, including a no. of breast cancer cell lines, predominantly express the REV-ERBβ variant. This pattern was independent of ERBB2 and ER status, and opposite to that of non-cancer mammary epithelial HMEC cells, in which REV-ERBα was the major variant. Consistent with this mol. profile, REV-ERB target genes in both circadian and metabolic pathways were derepressed upon silencing of REV-ERBβ, but not REV-ERBα. Strikingly, we found that REV-ERBβ is a determinant of sensitivity to chloroquine, a clin. relevant lysosomotropic agent that suppresses autophagy. The cytoprotective function of REV-ERBβ appears to operate downstream of autophagy blockade. Through compd. screening, we identified ARN5187, a novel lysosomotropic REV-ERBβ ligand with a dual inhibitory activity toward REV-ERB-mediated transcriptional regulation and autophagy. Remarkably, although ARN5187 and chloroquine share similar lysosomotropic potency and have a similar effect on autophagy inhibition, ARN5187 is significantly more cytotoxic. Collectively, our results reveal that dual inhibition of REV-ERBβ and autophagy is an effective strategy for eliciting cytotoxicity in cancer cells. Furthermore, our discovery of a novel inhibitor compd. of both REV-ERB and autophagy may provide a scaffold for the discovery of new multifunctional anticancer agents.
- 148Torrente, E.; Parodi, C.; Ercolani, L.; De Mei, C.; Ferrari, A.; Scarpelli, R.; Grimaldi, B. Synthesis and in Vitro Anticancer Activity of the First Class of Dual Inhibitors of REV-ERBβ and Autophagy. J. Med. Chem. 2015, 58 (15), 5900– 5915, DOI: 10.1021/acs.jmedchem.5b00511[ACS Full Text], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFWgs77I&md5=200ecfe72a200e5b1a944cd9ccac683aSynthesis and in Vitro Anticancer Activity of the First Class of Dual Inhibitors of REV-ERBβ and AutophagyTorrente, Esther; Parodi, Chiara; Ercolani, Luisa; De Mei, Claudia; Ferrari, Alessio; Scarpelli, Rita; Grimaldi, BenedettoJournal of Medicinal Chemistry (2015), 58 (15), 5900-5915CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Autophagy inhibition is emerging as a promising anticancer strategy. We recently reported that the circadian nuclear receptor REV-ERBβ plays an unexpected role in sustaining cancer cell survival when the autophagy flux is compromised. We also identified 4-[[[1-(2-fluorophenyl)cyclopentyl]amino]methyl]-2-[(4-methylpiperazin-1-yl)methyl]phenol, (I; ARN5187), as a novel dual inhibitor of REV-ERBβ and autophagy. I had improved cytotoxicity against BT-474 breast cancer cells compared to chloroquine, a clin. relevant autophagy inhibitor. Here, we present the results of structure-activity studies, based around I, that disclose the first class of dual inhibitors of REV-ERBβ and autophagy. This study led to identification of 1-(4-fluorophenyl)-N-[[3-[(4-methylpiperazin-1-yl)methyl]phenyl]methyl]cyclopentanamine trihydrochloride and 1-(2-fluorophenyl)-N-[[3-[(1-methyl-4-piperidyl)methyl]phenyl]methyl]cyclopentanamide dihydrochloride, which were more effective REV-ERBβ antagonists than I and were more cytotoxic to BT-474. The combination of optimal chem. and structural moieties of these analogs generated II, which elicited 15-fold greater REV-ERBβ inhibitory and cytotoxic activities compared to I. Furthermore, II induced death in a panel of tumor cell lines at doses 5-50 times lower than an equitoxic amt. of chloroquine but did not affect the viability of normal mammary epithelial cells.
- 149Dierickx, P.; Emmett, M. J.; Jiang, C.; Uehara, K.; Liu, M.; Adlanmerini, M.; Lazar, M. A. SR9009 Has REV-ERB–Independent Effects on Cell Proliferation and Metabolism. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (25), 12147– 12152, DOI: 10.1073/pnas.1904226116[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFyktr%252FI&md5=58bd9ff46809fd7f5dbec6fe7b86b4a3SR9009 has REV-ERB-independent effects on cell proliferation and metabolismDierickx, Pieterjan; Emmett, Matthew J.; Jiang, Chunjie; Uehara, Kahealani; Liu, Manlu; Adlanmerini, Marine; Lazar, Mitchell A.Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (25), 12147-12152CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The nuclear receptors REV-ERBα and -β link circadian rhythms and metab. Like other nuclear receptors, REV-ERB activity can be regulated by ligands, including naturally occurring heme. A putative ligand, SR9009, has been reported to elicit a range of beneficial effects in healthy as well as diseased animal models and cell systems. However, the direct involvement of REV-ERBs in these effects of SR9009 has not been thoroughly assessed, as expts. were not performed in the complete absence of both proteins. Here, we report the generation of a mouse model for conditional genetic deletion of REV-ERBα and -β. We show that SR9009 can decrease cell viability, rewire cellular metab., and alter gene transcription in hepatocytes and embryonic stem cells lacking both REV-ERBα and -β. Thus, the effects of SR9009 cannot be used solely as surrogate for REV-ERB activity.
- 150Moore, D. D.; Kato, S.; Xie, W.; Mangelsdorf, D. J.; Schmidt, D. R.; Xiao, R.; Kliewer, S. A. International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor α, Farnesoid X Receptor β, Liver X Receptor α, Liver X Receptor β, and Vitamin D Receptor. Pharmacol. Rev. 2006, 58 (4), 742– 759, DOI: 10.1124/pr.58.4.6[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1aisg%253D%253D&md5=0233111cc7b63bb16aeb179e7a6631e1International union of pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor α, farnesoid X receptor β, liver X receptor α, liver X receptor β, and vitamin D receptorMoore, David D.; Kato, Shigeaki; Xie, Wen; Mangelsdorf, David J.; Schmidt, Daniel R.; Xiao, Rui; Kliewer, Steven A.Pharmacological Reviews (2006), 58 (4), 742-759CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. The nuclear receptors of the NR1H and NR1I subgroups include the constitutive androstane receptor, pregnane X receptor, farnesoid X receptors, liver X receptors, and vitamin D receptor. The newly emerging functions of these related receptors are under the control of metabolic pathways, including metab. of xenobiotics, bile acids, cholesterol, and calcium. This review summarizes results of structural, pharmacol., and genetic studies of these receptors.
- 151Viennois, E.; Mouzat, K.; Dufour, J.; Morel, L.; Lobaccaro, J.-M.; Baron, S. Selective Liver X Receptor Modulators (SLiMs): What Use in Human Health?. Mol. Cell. Endocrinol. 2012, 351 (2), 129– 141, DOI: 10.1016/j.mce.2011.08.036[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtFSht7o%253D&md5=04988d1eea2056d01db65f2c1b49395bSelective liver X receptor modulators (SLiMs): What use in human health?Viennois, Emilie; Mouzat, Kevin; Dufour, Julie; Morel, Laurent; Lobaccaro, Jean-Marc; Baron, SilvereMolecular and Cellular Endocrinology (2012), 351 (2), 129-141CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ireland Ltd.)A review. Liver X receptors (LXR) are members of the nuclear receptor family. As activated transcription factors, their putative assocn. with human diseases makes them promising pharmacol. targets because of the large potential to develop ligands. LXR are mainly considered as intracellular cholesterol "sensors" whose activation leads to decreased plasma cholesterol. They also modulate numerous physiol. functions: fatty acid synthesis and metab., glucose homeostasis, steroidogenesis, immunity, and neurol. homeostasis. LXR-deficiency in mouse results in several phenotypes mimicking pathol. conditions in humans. This review will be focused on the various natural and synthetic LXR agonists and antagonists. Putative clin. targets including atherosclerosis, diabetes, Alzheimer's disease, skin disorders, and cancer will be covered.
- 152Mouzat, K.; Chudinova, A.; Polge, A.; Kantar, J.; Camu, W.; Raoul, C.; Lumbroso, S. Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases?. Int. J. Mol. Sci. 2019, 20 (16), 3858, DOI: 10.3390/ijms20163858[Crossref], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVCgsLY%253D&md5=e06731e71eff008739304a6972bb8f57Regulation of brain cholesterol: what role do liver X receptors play in neurodegenerative diseases?Mouzat, Kevin; Chudinova, Aleksandra; Polge, Anne; Kantar, Jovana; Camu, William; Raoul, Cedric; Lumbroso, SergeInternational Journal of Molecular Sciences (2019), 20 (16), 3858CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concns. and act as transcription factors to promote expression of target genes. Among their numerous physiol. roles, they act as central cholesterollowering factors. In the central nervous system (CNS), cholesterol has been shown to be an essential determinant of brain function, particularly as a major constituent of myelin and membranes. In the brain, LXRs act as cholesterol central regulators, and, beyond this metabolic function, LXRs have addnl. roles such as providing neuroprotective effects and lowering neuroinflammation. In many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis (MS), dysregulations of cholesterol and oxysterol have been reported. In this paper, we propose to focus on recent advances in the knowledge of the LXRs roles on brain cholesterol and oxysterol homeostasis, neuroinflammation, neuroprotection, and their putative involvement in neurodegenerative disorders. We will discuss their potential use as candidates for both mol. diagnosis and as promising pharmacol. targets in the treatment of ALS, AD, or MS patients.
- 153Hong, C.; Tontonoz, P. Liver X Receptors in Lipid Metabolism: Opportunities for Drug Discovery. Nature Reviews Drug Discovery 2014, 13, 433– 444, DOI: 10.1038/nrd4280[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXotV2iuro%253D&md5=1d7c39473460b5ecd5ea1c4a3ff18342Liver X receptors in lipid metabolism: opportunities for drug discoveryHong, Cynthia; Tontonoz, PeterNature Reviews Drug Discovery (2014), 13 (6), 433-444CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. The liver X receptors (LXRs) are pivotal regulators of lipid homeostasis in mammals. These transcription factors control the expression of a battery of genes involved in the uptake, transport, efflux and excretion of cholesterol in a tissue-dependent manner. The identification of the LXRs, and an increased understanding of the mechanisms by which LXR signalling regulates lipid homeostasis in different tissues (including the liver, intestine and brain), has highlighted new opportunities for therapeutic intervention in human metab. New strategies for the pharmacol. manipulation of LXRs and their target genes offer promise for the treatment of human diseases in which lipids have a central role, including atherosclerosis and Alzheimer's disease.
- 154Sodhi, R. K.; Singh, N. Liver X Receptors: Emerging Therapeutic Targets for Alzheimer’s Disease. Pharmacol Res. 2013, 72, 45– 51, DOI: 10.1016/j.phrs.2013.03.008[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnt1Sju7s%253D&md5=3dfb6bd42af9b006f95dc7753cd61622Liver X receptors: Emerging therapeutic targets for Alzheimer's diseaseSodhi, Rupinder K.; Singh, NirmalPharmacological Research (2013), 72 (), 45-51CODEN: PHMREP; ISSN:1043-6618. (Elsevier Ltd.)A review. Alzheimer's disease (AD) is a complex neurodegenerative disorder, typified by the pathol. accumulation of ss-amyloid peptides (Ass) and neurofibrillary tangles within the brain, culminating to cognitive impairment. Epidemiol. and biochem. data have suggested a link between cholesterol content, APP (amyloid precursor protein) processing, Ass, inflammation and AD. The intricacy of the disease presents considerable challenges for the development of newer therapeutic agents. Liver X receptors (LXRa and LXRss) are oxysterol activated nuclear receptors that play essential role in lipid and glucose homeostasis, steroidogenesis and inflammatory responses. LXR signalling impacts the development of AD pathol. through multiple pathways. Reports indicate that genetic loss of either lxra or lxrss in APP/PS1 transgenic mice results in increased amyloid plaque load. Studies also suggest that ligand activation of LXRs in Tg2576 mice enhanced, the expression of genes linked with cholesterol efflux e.g. apoe, abca-1, down regulated APP processing and Ass prodn. with significant improvement in memory functions. LXR agonists have also depicted to inhibit neuroinflammation through modulation of microglial phagocytosis and by repressing the expression of cox2, mcp1 and iNos in glial cells. This review summarizes in brief the biol. of LXRs, with an emphasis on their probable pathophysiol. mechanisms that may elicit the defending role of these receptors in brains of AD patients.
- 155Moutinho, M.; Landreth, G. E. Therapeutic Potential of Nuclear Receptor Agonists in Alzheimer’s Disease. J. Lipid Res. 2017, 58 (10), 1937– 1949, DOI: 10.1194/jlr.R075556[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFyltbbM&md5=ea824465a190d51f9c27180915217664Therapeutic potential of nuclear receptor agonists in Alzheimer's diseaseMoutinho, Miguel; Landreth, Gary E.Journal of Lipid Research (2017), 58 (10), 1937-1949CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology)A review. Alzheimer's disease (AD) is characterized by an extensive accumulation of amyloid-β (Aβ) peptide, which triggers a set of deleterious processes, including synaptic dysfunction, inflammation, and neuronal injury, leading to neuronal loss and cognitive impairment. A large body of evidence supports that nuclear receptor (NR) activation could be a promising therapeutic approach for AD. NRs are ligand-activated transcription factors that regulate gene expression and have cell type-specific effects. In this review, we discuss the mechanisms that underlie the beneficial effects of NRs in AD. Moreover, we summarize studies reported in the last 10-15 years and their major outcomes arising from the pharmacol. targeting of NRs in AD animal models. The dissection of the pathways regulated by NRs in the context of AD is of importance in identifying novel and effective therapeutic strategies.
- 156Björkhem, I.; Meaney, S. Brain Cholesterol: Long Secret Life behind a Barrier. Arterioscler., Thromb., Vasc. Biol. 2004, 24 (5), 806– 815, DOI: 10.1161/01.ATV.0000120374.59826.1b[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c3jtlKktw%253D%253D&md5=4273c1fb2054333fdeca963d01ba6fd8Brain cholesterol: long secret life behind a barrierBjorkhem Ingemar; Meaney SteveArteriosclerosis, thrombosis, and vascular biology (2004), 24 (5), 806-15 ISSN:.Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation. Under steady-state conditions, most of the de novo synthesis of cholesterol in the brain appears to be balanced by excretion of the cytochrome P-450-generated oxysterol 24S-hydroxycholesterol. This oxysterol is capable of escaping the recycling mechanism and traversing the blood-brain barrier. Cholesterol levels and cholesterol turnover are affected in neurodegenerating disorders, and the capacity for cholesterol transport and recycling in the brain seems to be of importance for the development of such diseases. The possibility has been discussed that administration of inhibitors of cholesterol synthesis may reduce the prevalence of Alzheimer disease. No firm conclusions can, however, be drawn from the studies presented thus far. In the present review, the most recent advances in our understanding of cholesterol turnover in the brain is discussed.
- 157Hussain, G.; Wang, J.; Rasul, A.; Anwar, H.; Imran, A.; Qasim, M.; Zafar, S.; Kamran, S. K. S.; Razzaq, A.; Aziz, N.; Ahmad, W.; Shabbir, A.; Iqbal, J.; Baig, S. M.; Sun, T. Role of Cholesterol and Sphingolipids in Brain Development and Neurological Diseases. Lipids in Health and Disease 2019, 18, 26, DOI: 10.1186/s12944-019-0965-z[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cjltl2qtQ%253D%253D&md5=1516cf800605ff20baced965dd872729Role of cholesterol and sphingolipids in brain development and neurological diseasesHussain Ghulam; Anwar Haseeb; Zafar Shamaila; Kamran Syed Kashif Shahid; Razzaq Aroona; Aziz Nimra; Ahmad Waseem; Wang Jing; Sun Tao; Rasul Azhar; Imran Ali; Qasim Muhammad; Shabbir Asghar; Iqbal Javed; Baig Shahid MahmoodLipids in health and disease (2019), 18 (1), 26 ISSN:.Brain is a vital organ of the human body which performs very important functions such as analysis, processing, coordination, and execution of electrical signals. For this purpose, it depends on a complex network of nerves which are ensheathed in lipids tailored myelin; an abundant source of lipids in the body. The nervous system is enriched with important classes of lipids; sphingolipids and cholesterol which compose the major portion of the brain particularly in the form of myelin. Both cholesterol and sphingolipids are embedded in the microdomains of membrane rafts and are functional units of the neuronal cell membrane. These molecules serve as the signaling molecules; hold important roles in the neuronal differentiation, synaptogenesis, and many others. Thus, their adequate provision and active metabolism are of crucial importance in the maintenance of physiological functions of brain and body of an individual. In the present review, we have highlighted the physiological roles of cholesterol and sphingolipids in the development of the nervous system as well as the association of their altered metabolism to neurological and neurodegenerative diseases.
- 158Mauch, D. H.; Nägler, K.; Schumacher, S.; Göritz, C.; Müller, E.-C.; Otto, A.; Pfrieger, F. W. CNS Synaptogenesis Promoted by Glia-Derived Cholesterol. Science 2001, 294 (5545), 1354– 1357, DOI: 10.1126/science.294.5545.1354[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXotlKmu7c%253D&md5=106cd66675d04553605f1a1cb57c6e5aCNS synaptogenesis promoted by glia-derived cholesterolMauch, Daniela H.; Naegler, Karl; Schumacher, Stefan; Goertzz, Christian; Mueller, Eva-Christina; Otto, Albrecht; Pfrieger, Frank W.Science (Washington, DC, United States) (2001), 294 (5545), 1354-1357CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The mol. mechanisms controlling synaptogenesis in the central nervous system (CNS) are poorly understood. Previous reports showed that a glia-derived factor strongly promotes synapse development in cultures of purified CNS neurons. Here, we identify this factor as cholesterol complexed to apolipoprotein E-contg. lipoproteins. CNS neurons produce enough cholesterol to survive and grow, but the formation of numerous mature synapses demands addnl. amts. that must be provided by glia. Thus, the availability of cholesterol appears to limit synapse development. This may explain the delayed onset of CNS synaptogenesis after glia differentiation and neurobehavioral manifestations of defects in cholesterol or lipoprotein homeostasis.
- 159Zhang, J.; Liu, Q. Cholesterol Metabolism and Homeostasis in the Brain. Protein Cell 2015, 6 (4), 254– 264, DOI: 10.1007/s13238-014-0131-3[Crossref], [PubMed], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvVent7k%253D&md5=8c80b65527e3c1bbfb12229146588a14Cholesterol metabolism and homeostasis in the brainZhang, Juan; Liu, QiangProtein & Cell (2015), 6 (4), 254-264CODEN: PCREFB; ISSN:1674-800X. (Higher Education Press)Cholesterol is an essential component for neuronal physiol. not only during development stage but also in the adult life. Cholesterol metab. in brain is independent from that in peripheral tissues due to blood-brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metab. has been shown to be implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and some cognitive deficits typical of the old age. The brain contains large amt. of cholesterol, but the cholesterol metab. and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metab. with mol. mechanisms.
- 160Abildayeva, K.; Jansen, P. J.; Hirsch-Reinshagen, V.; Bloks, V. W.; Bakker, A. H. F.; Ramaekers, F. C. S.; De Vente, J.; Groen, A. K.; Wellington, C. L.; Kuipers, F.; Mulder, M. 24(S)-Hydroxycholesterol Participates in a Liver X Receptor-Controlled Pathway in Astrocytes That Regulates Apolipoprotein E-Mediated Cholesterol Efflux. J. Biol. Chem. 2006, 281 (18), 12799– 12808, DOI: 10.1074/jbc.M601019200[Crossref], [PubMed], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjvFKktLs%253D&md5=13dccb379954c2902fd19ce86161ba8824(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol EffluxAbildayeva, Karlygash; Jansen, Paula J.; Hirsch-Reinshagen, Veronica; Bloks, Vincent W.; Bakker, Arjen H. F.; Ramaekers, Frans C. S.; de Vente, Jan; Groen, Albert K.; Wellington, Cheryl L.; Kuipers, Folkert; Mulder, MoniqueJournal of Biological Chemistry (2006), 281 (18), 12799-12808CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer disease (AD). It has been hypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes and neurons. However, the regulation of the cholesterol supply of neurons via apoE-contg. high d. lipoproteins remains to be clarified. We show for the first time that the brain-specific metabolite of cholesterol produced by neurons, i.e. 24(S)-hydroxycholesterol, induces apoE transcription, protein synthesis, and secretion in a dose- and time-dependent manner in cells of astrocytic but not of neuronal origin. Moreover, 24(S)-hydroxycholesterol primes astrocytoma, but not neuroblastoma cells, to mediate cholesterol efflux to apoE. Similar results were obtained using the synthetic liver X receptor (LXR) agonist GW683965A, suggesting involvement of an LXR-controlled signaling pathway. A 10-20-fold higher basal LXRα and -β expression level in astrocytoma compared with neuroblastoma cells may underlie these differential effects. Furthermore, apoE-mediated cholesterol efflux from astrocytoma cells may be controlled by the ATP binding cassette transporters ABCA1 and ABCG1, since their expression was also up-regulated by both compds. In contrast, ABCG4 seems not to be involved, because its expression was induced only in neuronal cells. The expression of sterol regulatory element-binding protein (SREBP-2), low d. lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and SREBP-1c was transiently up-regulated by GW683965A in astrocytes but down-regulated by 24(S)-hydroxycholesterol, suggesting that cholesterol efflux and synthesis are regulated independently. In conclusion, evidence is provided that 24(S)-hydroxycholesterol induces apoE-mediated efflux of cholesterol in astrocytes via an LXR-controlled pathway, which may be relevant for chronic and acute neurol. diseases.
- 161Peet, D. J.; Turley, S. D.; Ma, W.; Janowski, B. A.; Lobaccaro, J. M. A.; Hammer, R. E.; Mangelsdorf, D. J. Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα. Cell 1998, 93 (5), 693– 704, DOI: 10.1016/S0092-8674(00)81432-4[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjsl2ksb4%253D&md5=3f79fdf5390184cff2f5ee4653676e04Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXRαPeet, Daniel J.; Turley, Stephen D.; Ma, Wenzhen; Janowski, Bethany A.; Lobaccaro, Jean-Marc A.; Hammer, Robert E.; Mangelsdorf, David J.Cell (Cambridge, Massachusetts) (1998), 93 (5), 693-704CODEN: CELLB5; ISSN:0092-8674. (Cell Press)We demonstrate that mice lacking the oxysterol receptor, LXRα, lose their ability to respond normally to dietary cholesterol and are unable to tolerate any amt. of cholesterol in excess of that which they synthesize de novo. When fed diets contg. cholesterol, LXRα (-/-) mice fail to induce transcription of the gene encoding cholesterol 7α-hydroxylase (Cyp7a), the rate-limiting enzyme in bile acid synthesis. This defect is assocd. with a rapid accumulation of large amts. of cholesterol in the liver that eventually leads to impaired hepatic function. The regulation of several other crucial lipid metabolizing genes is also altered in LXRα (-/-) mice. These results demonstrate the existence of a physiol. significant feed-forward regulatory pathway for sterol metab. and establish the role of LXRα as the major sensor of dietary cholesterol.
- 162Andersson, S.; Gustafsson, N.; Warner, M.; Gustafsson, J.-Å. Inactivation of Liver X Receptor β Leads to Adult-Onset Motor Neuron Degeneration in Male Mice. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (10), 3857– 3862, DOI: 10.1073/pnas.0500634102[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXisVOgtL8%253D&md5=7952398d57bc6e6ecbca679d45b2016aInactivation of liver X receptor β leads to adult-onset motor neuron degeneration in male miceAndersson, Sandra; Gustafsson, Nina; Warner, Margaret; Gustafsson, Jan-AkeProceedings of the National Academy of Sciences of the United States of America (2005), 102 (10), 3857-3862CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Male mice with inactivated liver X receptor (LXR) β suffer from adult-onset motor neuron degeneration. By 7 mo of age, motor coordination is impaired, and this condition is assocd. with lipid accumulation and loss of motor neurons in the spinal cord, together with axonal atrophy and astrogliosis. Several of these features are reminiscent of the neuropathol. signs of chronic motor neuron disease such as amyotrophic lateral sclerosis. Because the LXRs are important for cholesterol and lipid metab., we speculate that absence of LXRβ leads to pathol. accumulation of sterols and lipids that may themselves be neurotoxic or may modulate intracellular pathways and thereby predispose motor neurons to degeneration.
- 163Bigini, P.; Steffensen, K. R.; Ferrario, A.; Diomede, L.; Ferrara, G.; Barbera, S.; Salzano, S.; Fumagalli, E.; Ghezzi, P.; Mennini, T.; Gustafsson, J.-Å. Neuropathologic and Biochemical Changes During Disease Progression in Liver X Receptor β –/– Mice, A Model of Adult Neuron Disease. J. Neuropathol. Exp. Neurol. 2010, 69 (6), 593– 605, DOI: 10.1097/NEN.0b013e3181df20e1[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslWhtr0%253D&md5=2d9fa70c51471c2670561984bb2df98eNeuropathologic and Biochemical Changes During Disease Progression in Liver X Receptor β-/- Mice, A Model of Adult Neuron DiseaseBigini, Paolo; Steffensen, Knut R.; Ferrario, Anna; Diomede, Luisa; Ferrara, Giovanni; Barbera, Sara; Salzano, Sonia; Fumagalli, Elena; Ghezzi, Pietro; Mennini, Tiziana; Gustafsson, Jan-ÅkeJournal of Neuropathology & Experimental Neurology (2010), 69 (6), 593-605CODEN: JNENAD; ISSN:0022-3069. (Lippincott Williams & Wilkins)In amyotrophic lateral sclerosis (ALS), there is selective degeneration of motor neurons that leads to paralysis and death. Although the etiol. of ALS is unclear, its heterogeneity suggests that a combination of factors (endogenous and/or environmental) may induce progressive motor neuron stress that results in the activation of different cell death pathways. Alterations of brain cholesterol homeostasis have recently been considered as possible cofactors in many neurodegenerative disorders, including ALS. The liver X receptor β (LXRβ) receptor is involved in lipogenesis and cholesterol metab., and we previously found that adult-onset motor neuron pathol. occurs in LXRβ mice. Here, we investigated neuromuscular alterations of LXRβ mice from ages 3 to 24 mo. Increased cholesterol levels, gliosis, and inflammation preceded motor neuron loss and clin. disease onset; the mice showed progressive motor neuron deficits starting from age 7 mo. The nos. of motor neurons and neuromuscular junctions were decreased in 24-mo-old mice, but neither paralysis nor reduced life span was obsd. Moreover, other spinal neurons were also lost in these mice. These results suggest that LXRβ may inhibit neuroinflammation and maintain cholesterol homeostasis, and that LXRβ mice represent a potential model for investigating the role of cholesterol in ALS and other neurodegenerative disorders.
- 164Meffre, D.; Shackleford, G.; Hichor, M.; Gorgievski, V.; Tzavara, E. T.; Trousson, A.; Ghoumari, A. M.; Deboux, C.; Oumesmar, B. N.; Liere, P.; Schumacher, M.; Baulieu, E.-E.; Charbonnier, F.; Grenier, J.; Massaad, C. Liver X Receptors Alpha and Beta Promote Myelination and Remyelination in the Cerebellum. Proc. Natl. Acad. Sci. U. S. A. 2015, 112 (24), 7587– 7592, DOI: 10.1073/pnas.1424951112[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptFShsL4%253D&md5=1835e42bc70fc4c62c299aedb6dfdb6cLiver X receptors alpha and beta promote myelination and remyelination in the cerebellumMeffre, Delphine; Shackleford, Ghjuvan'Ghjacumu; Hichor, Mehdi; Gorgievski, Victor; Tzavara, Eleni T.; Trousson, Amalia; Ghoumari, Abdel M.; Deboux, Cyrille; Oumesmar, Brahim Nait; Liere, Philippe; Schumacher, Michael; Baulieu, Etienne-Emile; Charbonnier, Frederic; Grenier, Julien; Massaad, CharbelProceedings of the National Academy of Sciences of the United States of America (2015), 112 (24), 7587-7592CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The identification of new pathways governing myelination provides innovative avenues for remyelination. Liver X receptors (LXRs) α and β are nuclear receptors activated by oxysterols that originated from the oxidn. of cholesterol. They are crucial for cholesterol homeostasis, a major lipid constituent of myelin sheaths that are formed by oligodendrocytes. However, the role of LXRs in myelin generation and maintenance is poorly understood. Here, we show that LXRs are involved in myelination and remyelination processes. LXRs and their ligands are present in oligodendrocytes. We found that mice invalidated for LXRs exhibit altered motor coordination and spatial learning, thinner myelin sheaths, and reduced myelin gene expression. Conversely, activation of LXRs by either 25-hydroxycholesterol or synthetic TO901317 stimulates myelin gene expression at the promoter, mRNA, and protein levels, directly implicating LXRα/β in the transcriptional control of myelin gene expression. Interestingly, activation of LXRs also promotes oligodendroglial cell maturation and remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Together, our findings represent a conceptual advance in the transcriptional control of myelin gene expression and strongly support a new role of LXRs as pos. modulators in central (re)myelination processes.
- 165Song, X.-Y.; Wu, W.-F.; Gabbi, C.; Dai, Y.-B.; So, M.; Chaurasiya, S. P.; Wang, L.; Warner, M.; Gustafsson, J. Å. Retinal and Optic Nerve Degeneration in Liver X Receptor β Knockout Mice. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (33), 16507– 16512, DOI: 10.1073/pnas.1904719116[Crossref], [PubMed], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFylsLfJ&md5=9c9c2d8ee91b742de28c7018f3009e9bRetinal and optic nerve degeneration in liver X receptor β knockout miceSong, Xiao-yu; Wu, Wan-fu; Gabbi, Chiara; Dai, Yu-bing; So, Mark; Chaurasiya, Surendra P.; Wang, Li; Warner, Margaret; Gustafsson, Jan-AakeProceedings of the National Academy of Sciences of the United States of America (2019), 116 (33), 16507-16512CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The retina is an extension of the brain. Like the brain, neurodegeneration of the retina occurs with age and is the cause of several retinal diseases including optic neuritis, macular degeneration, and glaucoma. Liver X receptors (LXRs) are expressed in the brain where they play a key role in maintenance of cerebrospinal fluid and the health of dopaminergic neurons. Herein, we report that LXRs are expressed in the retina and optic nerve and that loss of LXRβ, but not LXRα, leads to loss of ganglion cells in the retina. In the retina of LXRβ-/- mice, there is an increase in amyloid A4 and deposition of beta-amyloid (Aβ) aggregates but no change in the level of apoptosis or autophagy in the ganglion cells and no activation of microglia or astrocytes. However, in the optic nerve there is a loss of aquaporin 4 (AQP4) in astrocytes and an increase in activation of microglia. Since loss of AQP4 and microglial activation in the optic nerve precedes the loss of ganglion cells, and accumulation of Aβ in the retina, the cause of the neuronal loss appears to be optic nerve degeneration. In patients with optic neuritis there are frequently AQP4 autoantibodies which block the function of AQP4. LXRβ-/- mouse is another model of optic neuritis in which AQP4 antibodies are not detectable, but AQP4 function is lost because of redn. in its expression.
- 166Zelcer, N.; Khanlou, N.; Clare, R.; Jiang, Q.; Reed-Geaghan, E. G.; Landreth, G. E.; Vinters, H. V.; Tontonoz, P. Attenuation of Neuroinflammation and Alzheimer’s Disease Pathology by Liver x Receptors. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (25), 10601– 10606, DOI: 10.1073/pnas.0701096104[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnt1Oisrs%253D&md5=2e39b726deba9673ce5a76f2e864789eAttenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptorsZelcer, Noam; Khanlou, Negar; Clare, Ryan; Jiang, Qingguang; Reed-Geaghan, Erin G.; Landreth, Gary E.; Vinters, Harry V.; Tontonoz, PeterProceedings of the National Academy of Sciences of the United States of America (2007), 104 (25), 10601-10606CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metab. and inflammation, processes that can be modulated by liver x receptors (LXRs). We show here that endogenous LXR signaling impacts the development of AD-related pathol. Genetic loss of either Lxrα or Lxrβ in APP/PS1 transgenic mice results in increased amyloid plaque load. LXRs regulate basal and inducible expression of key cholesterol homeostatic genes in the brain and act as potent inhibitors of inflammatory gene expression. Ligand activation of LXRs attenuates the inflammatory response of primary mixed glial cultures to fibrillar amyloid β peptide (fAβ) in a receptor-dependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fAβ-stimulated phagocytosis in the setting of inflammation. These results identify endogenous LXR signaling as an important determinant of AD pathogenesis in mice. We propose that LXRs may be tractable targets for the treatment of AD due to their ability to modulate both lipid metabolic and inflammatory gene expression in the brain.
- 167Cui, W.; Sun, Y.; Wang, Z.; Xu, C.; Peng, Y.; Li, R. Liver X Receptor Activation Attenuates Inflammatory Response and Protects Cholinergic Neurons in APP/PS1 Transgenic Mice. Neuroscience 2012, 210, 200– 210, DOI: 10.1016/j.neuroscience.2012.02.047[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xntlahsbo%253D&md5=853f54f01e6dc13814e7497df19636c8Liver X receptor activation attenuates inflammatory response and protects cholinergic neurons in APP/PS1 transgenic miceCui, W.; Sun, Y.; Wang, Z.; Xu, C.; Peng, Y.; Li, R.Neuroscience (Amsterdam, Netherlands) (2012), 210 (), 200-210CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)Alzheimer's disease (AD) is assocd. with beta-amyloid deposition, glial activation, and increased levels of the cytokines, as well as cholinergic dysfunction. Liver X receptor (LXR) has been found to inhibit the expression of pro-inflammatory genes. However, the effects of LXR activation on inflammatory response and on cholinergic system in AD are not yet clear. The present results revealed that LXR activation markedly attenuated several inflammatory markers and decreased microglial activation and reactive astrocytes in amyloid precursor protein (APP)/PS1 transgenic mice. Addnl., LXR activation significantly increased the no. of cholinergic neurons in the medial septal regions and the basal nucleus of Meynert (NBM), and attenuated cognitive impairment. Furthermore, we obsd. that LXR activation inhibited the prodn. of COX-2 and iNOS from Aβ25-35-induced microglia. LXR activation and nuclear factor kappa B (NF-κB) inhibitor PDTC both attenuated Aβ25-35 induction of NF-κB activation. These results suggest that LXR agonists suppress the prodn. of pro-inflammatory mols., at least in part, by modulating NF-κB-signaling pathway. Collectively, these studies suggest that LXR agonists may have therapeutic significance in AD.
- 168Strittmatter, W. J.; Saunders, A. M.; Schmechel, D.; Pericak-Vance, M.; Enghild, J.; Salvesen, G. S.; Roses, A. D. Apolipoprotein E: High-Avidity Binding to β-Amyloid and Increased Frequency of Type 4 Allele in Late-Onset Familial Alzheimer Disease. Proc. Natl. Acad. Sci. U. S. A. 1993, 90 (5), 1977– 1981, DOI: 10.1073/pnas.90.5.1977[Crossref], [PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXhs1Klsrs%253D&md5=a9c5fafcf128fc2c9dbe4f66a26d1981Apolipoprotein E: High-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer diseaseStrittmatter, Warren J.; Saunders, Ann M.; Schmechel, Donald; Pericak-Vance, Margaret; Enghild, Jan; Salvesen, Guy S.; Roses, Allen D.Proceedings of the National Academy of Sciences of the United States of America (1993), 90 (5), 1977-81CODEN: PNASA6; ISSN:0027-8424.Apolipoprotein E is immunochem. localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic βA4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-18 of the βA4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously assocd. with linkage of late-onset familial Alzheimer disease. Anal. of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant assocn. of apolipoprotein E type 4 allele (APOE-ε4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-ε4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50; the allele frequency of APOE-ε4 in 91 age-matched unrelated controls was 0.16 (Z = 2.44, P = 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.
- 169Pitas, R. E.; Boyles, J. K.; Lee, S. H.; Foss, D.; Mahley, R. W. Astrocytes Synthesize Apolipoprotein E and Metabolize Apolipoprotein E-Containing Lipoproteins. Biochim. Biophys. Acta, Lipids Lipid Metab. 1987, 917 (1), 148– 161, DOI: 10.1016/0005-2760(87)90295-5[Crossref], [PubMed], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2sXot1SntA%253D%253D&md5=9b8e51955e70b3ca56db292e5ec9efb0Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteinsPitas, Robert E.; Boyles, Janet K.; Lee, Susan H.; Foss, Donna; Mahley, Robert W.Biochimica et Biophysica Acta, Lipids and Lipid Metabolism (1987), 917 (1), 148-61CODEN: BBLLA6; ISSN:0005-2760.Primary cultures of rat brain astrocytes were used to study apolipoprotein E synthesis, secretion, and metab. in vitro. The astrocytes in culture contained immunoreactive apolipoprotein E in the area of the Golgi app. Incubation of the astrocytes with [35S]methionine resulted in the secretion of labeled immunoprecipitable apolipoprotein E, which constituted 1-3% of the total secreted proteins. The apolipoprotein E secreted in culture and the apolipoprotein E in rat brain exts. differed from serum apolipoprotein E in 2 respects: both had a slightly higher apparent mol. wt. (∼36,000) and more acidic isoforms than serum apolipoprotein E. Sialylation of the newly secreted apolipoprotein accounted for the difference in both the apparent mol. wt. and isoelec. focusing pattern of newly secreted apolipoprotein E and plasma apolipoprotein E. The astrocytes possessed apolipoprotein B,E[low-d. lipoprotein(LDL)] receptors capable of binding and internalizing apolipoprotein E-contg. lipoproteins. The uptake of lipoproteins by the cells led to a redn. in the no. of cell surface receptors and to the intracellular accumulation of cholesteryl esters. Since apolipoprotein E is present within the brain, and since brain cells can express apolipoprotein B,E(LDL) receptors, apolipoprotein E-contg. lipoproteins may function to redistribute lipid and regulate cholesterol homeostasis within the brain.
- 170Ignatius, M. J.; Gebicke-Harter, P. J.; Skene, J. H.; Schilling, J. W.; Weisgraber, K. H.; Mahley, R. W.; Shooter, E. M. Expression of Apolipoprotein E during Nerve Degeneration and Regeneration. Proc. Natl. Acad. Sci. U. S. A. 1986, 83 (4), 1125– 1129, DOI: 10.1073/pnas.83.4.1125[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL28Xht1OgsLw%253D&md5=6f97affa572e92c94c4233e8ebfdfa2cExpression of apolipoprotein E during nerve degeneration and regenerationIgnatius, Michael J.; Gebicke-Haerter, Peter J.; Skene, J. H. Pate; Schilling, James W.; Weisgraber, Karl H.; Mahley, Robert W.; Shooter, Eric M.Proceedings of the National Academy of Sciences of the United States of America (1986), 83 (4), 1125-9CODEN: PNASA6; ISSN:0027-8424.A 37-kilodalton (kDa) glycoprotein, the synthesis of which is dramatically increased after injury of the rat sciatic and optic nerves, has been recently described. Extensive homol. was found between the 37-kDa nerve injury-induced protein and a well-studied serum protein, apolipoprotein E (apoE), that is involved in lipid and cholesterol metab. and that has been shown recently to be present in adult and developing rat astroglia. Both proteins had identical isoelec. focusing points and similar mol. masses. Antibodies raised against the 37-kDa protein recognized apoE and anti-apoE serum crossreacted with the 37-kDa protein. Sequence data for 2 14-amino acid stretches of the 37-kDa protein matched identical regions of apoE. Evidently, the 37-kDa protein is identical to serum apoE and could have functions similar to the latter.
- 171Fukumoto, H.; Deng, A.; Irizarry, M. C.; Fitzgerald, M. L.; Rebeck, G. W. Induction of the Cholesterol Transporter ABCA1 in Central Nervous System Cells by Liver X Receptor Agonists Increases Secreted Aβ Levels. J. Biol. Chem. 2002, 277 (50), 48508– 48513, DOI: 10.1074/jbc.M209085200[Crossref], [PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xptlegt7w%253D&md5=f1051a16f6d6e56e0f5f7d703a0f41c7Induction of the Cholesterol Transporter ABCA1 in Central Nervous System Cells by Liver X Receptor Agonists Increases Secreted Aβ LevelsFukumoto, Hiroaki; Deng, Amy; Irizarry, Michael C.; Fitzgerald, Michael L.; Rebeck, G. WilliamJournal of Biological Chemistry (2002), 277 (50), 48508-48513CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The expression, function, and regulation of the cholesterol efflux mol., ABCA1, has been extensively examd. in peripheral tissues but only poorly studied in the brain. Brain cholesterol metab. is of interest because several lines of evidence suggest that elevated cholesterol increases the risk of Alzheimer's disease. We found a largely neuronal expression of ABCA1 in normal rat brain by in situ hybridization. ABCA1 message was dramatically up-regulated in neurons and glia in areas of damage by hippocampal AMPA lesion after 3-7 days. Immunoblot anal. demonstrated ABCA1 protein in cultured neuronal and glial cells, and expression was induced by ligands of the nuclear hormone receptors of the retinoid X receptor and liver X receptor family. ABCA1 was induced by treatment with retinoic acid and several oxysterols, including 22(R)-hydroxycholesterol and 24-hydroxycholesterol. Expression of an ABCA1-green fluorescent protein construct in neuroblastoma cells demonstrated fluorescence in perinuclear compartments and on the plasma membrane. Because the Aβ peptide is important in Alzheimer's disease pathogenesis, we examd. whether ABCA1 induction altered Aβ levels. Treatment of neuroblastoma cells with retinoic acid and 22(R)-hydroxycholesterol caused significant increases in secreted Aβ40 (29%) and Aβ42 (65%). Treatment with a nonsteroidal liver X receptor ligand, TO-901317, similarly increased levels of secreted Aβ40 (25%) and Aβ42 (126%). The increase in secreted Aβ levels was reduced by RNAi blocking of ABCA1 expression. These data suggest that the cholesterol efflux mol. ABCA1 may also be involved in the secretion of the membrane-assocd. mol., Aβ.
- 172Sun, Y.; Yao, J.; Kim, T.-W.; Tall, A. R. Expression of Liver X Receptor Target Genes Decreases Cellular Amyloid β Peptide Secretion. J. Biol. Chem. 2003, 278 (30), 27688– 27694, DOI: 10.1074/jbc.M300760200[Crossref], [PubMed], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXlsFKktL4%253D&md5=6446e277ab3b67d722fcaca51363a6d5Expression of Liver X Receptor Target Genes Decreases Cellular Amyloid β Peptide SecretionSun, Yu; Yao, Jun; Kim, Tae-Wan; Tall, Alan R.Journal of Biological Chemistry (2003), 278 (30), 27688-27694CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)A hallmark of Alzheimer's disease is the deposition of plaques of amyloid β peptide (Aβ) in the brain. Aβ is thought to be formed from the amyloid precursor protein (APP) in cholesterol-enriched membrane rafts, and cellular cholesterol depletion decreases Aβ formation. The liver X receptors (LXR) play a key role in regulating genes that control cellular cholesterol efflux and membrane compn. and are widely expressed in cells of the central nervous system. We show that treatment of APP-expressing cells with LXR activators reduces the formation of Aβ. LXR activation resulted in increased levels of the ATP-binding cassette transporter A1 (ABCA1) and stearoyl CoA desaturase, and expression of these genes individually decreased formation of Aβ. Expression of ABCA1 led to both decreased β-cleavage product of APPSw (i.e. C99 peptide) and reduced γ-secretase-cleavage of C99 peptide. Remarkably, these effects of ABCA1 on APP processing were independent of cellular lipid efflux. LXR and ABCA1-induced changes in membrane lipid organization had favorable effects on processing of APP, suggesting a new approach to the treatment of Alzheimer's disease.
- 173Koldamova, R. P.; Lefterov, I. M.; Staufenbiel, M.; Wolfe, D.; Huang, S.; Glorioso, J. C.; Walter, M.; Roth, M. G.; Lazo, J. S. The Liver X Receptor Ligand T0901317 Decreases Amyloid β Production in Vitro and in a Mouse Model of Alzheimer’s Disease. J. Biol. Chem. 2005, 280 (6), 4079– 4088, DOI: 10.1074/jbc.M411420200[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVyntLc%253D&md5=8657c90b7ef8247998470773ed5f024bThe Liver X Receptor Ligand T0901317 Decreases Amyloid β Production in Vitro and in a Mouse Model of Alzheimer's DiseaseKoldamova, Radosveta P.; Lefterov, Iliya M.; Staufenbiel, Matthias; Wolfe, Darren; Huang, Shaohua; Glorioso, Joseph C.; Walter, Michael; Roth, Michael G.; Lazo, John S.Journal of Biological Chemistry (2005), 280 (6), 4079-4088CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Recent studies indicate that oxysterols, which are ligands for the nuclear hormone liver X receptors (LXR), decrease amyloid β (Aβ) secretion in vitro. The effect was attributed primarily to the ATP-binding cassette transporter A1 (ABCA1) transcriptionally up-regulated by ligand-activated LXRs. The authors now examd. the effect of the synthetic LXR ligand T0901317, which can be used in vivo, on Aβ prodn. in vitro and in APP23 transgenic mice. T0901317 applied to a variety of in vitro models, including immortalized fibroblasts from Tangier patients, and primary embryonic mouse neurons caused a concn.-dependent decrease in Aβ secretion, and this effect was increased by the addn. of apolipoprotein A-I. The inhibition of Aβ prodn. by T0901317 was cell-type specific, being more prominent in primary neurons than in nonneuronal cells. Tangier fibroblasts lacking a functional ABCA1 secreted more Aβ than control fibroblasts, thus demonstrating the role of ABCA1 in amyloid precursor protein (APP) processing and Aβ generation. T0901317 treatment of 11-wk-old APP23 mice for 6 days showed a significant increase in ABCA1 expression and a decrease in the ratio of sol. APP (sAPP)β- to sAPPα-cleavage products. Most importantly, the treatment caused a statistically significant redn. in the levels of sol. Aβ40 and of Aβ42 in the brain these mice. Our expts. demonstrate that T0901317 decreases amyloidogenic processing of APP in vitro and in vivo, thus supporting the search for potent and specific LXR ligands with properties allowing therapeutic application.
- 174Fitz, N. F.; Cronican, A.; Pham, T.; Fogg, A.; Fauq, A. H.; Chapman, R.; Lefterov, I.; Koldamova, R. Liver X Receptor Agonist Treatment Ameliorates Amyloid Pathology and Memory Deficits Caused by High-Fat Diet in APP23 Mice. J. Neurosci. 2010, 30 (20), 6862– 6872, DOI: 10.1523/JNEUROSCI.1051-10.2010[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovVWnurc%253D&md5=dee2ded5f2bf53a49f5621a618fe75a1Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 miceFitz, Nicholas F.; Cronican, Andrea; Pham, Tam; Fogg, Allison; Fauq, Abdul H.; Chapman, Robert; Lefterov, Iliya; Koldamova, RadosvetaJournal of Neuroscience (2010), 30 (20), 6862-6872CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)High-fat diet and certain dietary patterns are assocd. with higher incidence of sporadic Alzheimer's disease (AD) and cognitive decline. However, no specific therapy has been suggested to ameliorate the neg. effects of high fat/high cholesterol levels on cognition and amyloid pathol. Here we show that in 9-mo-old APP23 mice, a high-fat/high-cholesterol (HF) diet provided for 4 mo exacerbates the AD phenotype evaluated by behavioral, morphol., and biochem. assays. To examine the therapeutic potential of liver X receptor (LXR) ligands, APP23 mice were fed HF diet supplemented with synthetic LXR agonist T0901317 (T0). Our results demonstrate that LXR ligand treatment causes a significant redn. of memory deficits obsd. during both acquisition and retention phases of the Morris water maze. Moreover, the effects of T0 on cognition correlate with AD-like morphol. and biochem. parameters. We found a significant decrease in amyloid plaque load, insol. Aβ and sol. Aβ oligomers. In vitro expts. with primary glia demonstrate that Abca1 is essential for the proper lipidation of ApoE and mediates the effects of T0 on Aβ degrdn. by microglia. Microdialysis expts. performed on awake freely moving mice showed that T0 decreased Aβ levels in the interstitial fluid of the hippocampus, supporting the conclusion that this treatment increases Aβ clearance. The data presented conclusively shows that LXR activation in the context of a metabolic challenge has crit. effects on AD phenotype progression by attenuating Aβ deposition and facilitating its clearance.
- 175Cui, W.; Sun, Y.; Wang, Z.; Xu, C.; Xu, L.; Wang, F.; Chen, Z.; Peng, Y.; Li, R. Activation of Liver x Receptor Decreases BACE1 Expression and Activity by Reducing Membrane Cholesterol Levels. Neurochem. Res. 2011, 36 (10), 1910– 1921, DOI: 10.1007/s11064-011-0513-3[Crossref], [PubMed], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmslymsb4%253D&md5=aae2a483da4c4b349b0b8e79166890beActivation of liver X receptor decreases BACE1 expression and activity by reducing membrane cholesterol levelsCui, Weigang; Sun, Yan; Wang, Zhongping; Xu, Chongchong; Xu, Li; Wang, Fei; Chen, Zulin; Peng, Yuwen; Li, RuixiNeurochemical Research (2011), 36 (10), 1910-1921CODEN: NEREDZ; ISSN:0364-3190. (Springer)The synthetic Liver X receptor (LXR) activator T0901317 has been reported to exert neuroprotective effect in Alzheimer's disease, but the relationship between LXR activation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) remains uncertain. This study investigated the effect of T0901317 on membrane cholesterol levels, BACE1 expression and activity. We found that T0901317 decreased membrane cholesterol levels, reduced BACE1 expression and activity as well as β-secretase cleaved C-terminal fragment (β-CTF) levels in vivo and in vitro. Meanwhile, the expression of ATP-binding membrane cassette transport protein A1 (ABCA1) enhanced. Addnl., inhibition of ABCA1 abrogated the effects of T0901317 on membrane cholesterol levels and β-secretase activity. Moreover, addn. of LXR antagonist reversed the effect of T0901317 on ABCA1 mRNA expression, membrane cholesterol levels and β-secretase activity. Our results suggest that activation of LXR may decrease BACE1 expression and activity through a pathway assocd. with ABCA1-mediated redn. in membrane cholesterol levels.
- 176Wang, Q.; Wang, S.; Shi, Y.; Yao, M.; Hou, L.; Jiang, L. Reduction of Liver X Receptor β Expression in Primary Rat Neurons by Antisense Oligodeoxynucleotides Decreases Secreted Amyloid β Levels. Neurosci. Lett. 2014, 561, 146– 150, DOI: 10.1016/j.neulet.2013.12.055[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVWrtbw%253D&md5=6bf4cc34a1ff79d2ab2925bc054c469eReduction of Liver X Receptor β expression in primary rat neurons by antisense oligodeoxynucleotides decreases secreted amyloid β levelsWang, Qie; Wang, Suling; Shi, Yun; Yao, Min; Hou, Lianguo; Jiang, LinglingNeuroscience Letters (2014), 561 (), 146-150CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Ligand-activated Liver X Receptor (LXR) is known to increase cholesterol efflux from cells and reduce the prodn. of amyloid β (Aβ) from amyloid-beta precursor protein (APP). However, little is known about the effects of LXRβ, one subtype of LXR, on endogenous Aβ. In this study, we show that LXRβ inactivation with specific antisense oligodeoxynucleotides (As-ODN) significantly reduced secreted Aβ and decreased mRNA levels of APP751+770, and α-, β-secretase (ADAM10, BACE1) in primary rat neurons. We also show that As-ODN down-regulated the LXR responsive genes ABCA1 and HMG-CoA reductase (HMGCR). These changes are assocd. with decreased cellular cholesterol levels. The effect of LXRβ inactivation on Aβ levels is likely due to the alteration of cholesterol prodn. and APP processing. Thus, our data suggest that LXRβ has an important function in cholesterol homeostasis and endogenous Aβ maintenance in neurons.
- 177Vanmierlo, T.; Rutten, K.; Dederen, J.; Bloks, V. W.; van Vark-van der Zee, L. C.; Kuipers, F.; Kiliaan, A.; Blokland, A.; Sijbrands, E. J. G.; Steinbusch, H.; Prickaerts, J.; Lütjohann, D.; Mulder, M. Liver X Receptor Activation Restores Memory in Aged AD Mice without Reducing Amyloid. Neurobiol. Aging 2011, 32 (7), 1262– 1272, DOI: 10.1016/j.neurobiolaging.2009.07.005[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntlGjt7k%253D&md5=fa153f5dedceb7e40c084e4d6a14bcb4Liver X receptor activation restores memory in aged AD mice without reducing amyloidVanmierlo, Tim; Rutten, Kris; Dederen, Jos; Bloks, Vincent W.; van Vark-van der Zee, Leonie C.; Kuipers, Folkert; Kiliaan, Amanda; Blokland, Arjan; Sijbrands, Eric J. G.; Steinbusch, Harry; Prickaerts, Jos; Luetjohann, Dieter; Mulder, MoniqueNeurobiology of Aging (2011), 32 (7), 1262-1272CODEN: NEAGDO; ISSN:0197-4580. (Elsevier)Alterations in cerebral cholesterol metab. are thought to play a role in the progression of Alzheimer's disease (AD). Liver X receptors (LXRs) are key regulators of cholesterol metab. The synthetic LXR activator, T0901317 has been reported to improve memory functions in animal models for AD and to reduce amyloid-β (Aβ) deposition in the brain. Here we provide evidence that long-term administration of T0901317 to aged, 21-mo-old APPSLxPS1mut mice restores impaired memory. Cerebral cholesterol turnover was enhanced as indicated by the increased levels of brain cholesterol precursors and the upregulation of LXR-target genes Abca1, Abcg1, and Apoe. Unexpectedly, the improved memory functions in the APPSLxPS1mut mice after T0901317 treatment were not accompanied by a decrease in Aβ plaque load in the cortex or hippocampus DG, CA1 or CA3. T0901317 administration also enhanced cerebral cholesterol turnover in aged C57BL/6NCrl mice, but did not further improve their memory functions. In conclusion, long-term activation of the LXR-pathway restored memory functions in aged APPSLxPS1mut mice with advanced Aβ deposition. However the beneficial effects of T0901317 on memory in the APPSLxPS1mut mice were independent of the Aβ plaque load in the hippocampus, but were assocd. with enhanced brain cholesterol turnover.
- 178Sandoval-Hernández, A. G.; Buitrago, L.; Moreno, H.; Cardona-Gómez, G. P.; Arboleda, G. Role of Liver X Receptor in AD Pathophysiology. PLoS One 2015, 10 (12), e0145467, DOI: 10.1371/journal.pone.0145467[Crossref], [PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksFSjsr0%253D&md5=e9c8dc97778ff0d2afd1f0f48aa9da10Role of liver X receptor in AD pathophysiologySandoval-Hernandez, Adrian G.; Buitrago, Luna; Moreno, Herman; Cardona-Gomez, Gloria Patricia; Arboleda, GonzaloPLoS One (2015), 10 (12), e0145467/1-e0145467/24CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacol. activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are assocd. with improvement in cognition and redn. of amyloid beta pathol. in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-mo-old; three months treatment). The data suggests that the LXR agonist GW3965 is assocd. with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable redn. of the amyloid load. We also report that most cells overexpressing ApoE (86 ± 12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also obsd. redn. in astrogliosis and increased no. of stem and proliferating cells in the subgranular zone of the dentate gyrus. Addnl., we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/mol. mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.
- 179Báez-Becerra, C.; Filipello, F.; Sandoval-Hernández, A.; Arboleda, H.; Arboleda, G. Liver X Receptor Agonist GW3965 Regulates Synaptic Function upon Amyloid Beta Exposure in Hippocampal Neurons. Neurotoxic. Res. 2018, 33 (4), 569– 579, DOI: 10.1007/s12640-017-9845-3[Crossref], [PubMed], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlGltg%253D%253D&md5=d0aea58662132947b8c67aba38394808Liver X Receptor Agonist GW3965 Regulates Synaptic Function upon Amyloid Beta Exposure in Hippocampal NeuronsBaez-Becerra, C.; Filipello, F.; Sandoval-Hernandez, A.; Arboleda, H.; Arboleda, G.Neurotoxicity Research (2018), 33 (3), 569-579CODEN: NURRFI; ISSN:1029-8428. (Springer)Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by beta-amyloid (Aβ) accumulation and neurofibrillary tangles formation in the brain which are assocd. to synaptic deficits and dementia. Liver X receptor (LXR) agonists have been demonstrated to revert of pathol. and cognitive defects in murine models of AD through the regulation of Apolipoprotein E, ATP-Binding Cassette A1 (ABCA1), by dampening neuroinflammation and also by reducing the levels of amyloid-β (Aβ) accumulation in the brain. However, the role of LXR with regard to the regulation of synaptic function remains relatively understudied. In the present paper, we analyzed the in-vitro effect of the LXR agonist GW3965 on synaptic function upon exposure of primary hippocampal cultures to oligomeric amyloid-β (oAβ(1-42)). We showed that oAβ(1-42) exposure significantly decreased the d. of mature (mushroom shaped) dendritic spines d. and synaptic contacts no. oAβ(1-42) also modulates the expression of pre- (VGlut1, SYT1, SV2A) and post-synaptic (SHANK2, NMDA) proteins, it decreases the expression of PINK1, and increases ROCKII, and activates of caspase-3; these changes were prevented by the pre-treating neuronal cultures with GW3965. These results show further support the role of the LXR agonist GW3965 in synaptic physiol. and highlight its potential as an alternative pharmacol. strategy for AD.
- 180Kumar, N.; Solt, L. A.; Conkright, J. J.; Wang, Y.; Istrate, M. A.; Busby, S. A.; Garcia-Ordonez, R. D.; Burris, T. P.; Griffin, P. R. The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2- Trifluoro-1-Hydroxy-1-(Trifluoromethyl)Ethyl]Phenyl]-Benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist. Mol. Pharmacol. 2010, 77 (2), 228– 236, DOI: 10.1124/mol.109.060905[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFeitLk%253D&md5=04aaf2bdef4b9d64340e221f85838665The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-α/γ inverse agonistKumar, Naresh; Solt, Laura A.; Conkright, Juliana J.; Wang, Yongjun; Istrate, Monica A.; Busby, Scott A.; Garcia-Ordonez, Ruben D.; Burris, Thomas P.; Griffin, Patrick R.Molecular Pharmacology (2010), 77 (2), 228-236CODEN: MOPMA3; ISSN:0026-895X. (American Society for Pharmacology and Experimental Therapeutics)Retinoic acid receptor-related orphan receptors (RORs) regulate a variety of physiol. processes including hepatic gluconeogenesis, lipid metab., circadian rhythm, and immune function. Here we present the first high-affinity synthetic ligand for both RORα and RORγ. In a screen against all 48 human nuclear receptors, the benzenesulfonamide liver X receptor (LXR) agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) inhibited transactivation activity of RORα and RORγ but not RORβ. T0901317 was found to directly bind to RORα and RORγ with high affinity (Ki = 132 and 51 nM, resp.), resulting in the modulation of the receptor's ability to interact with transcriptional cofactor proteins. T0901317 repressed RORα/γ-dependent transactivation of ROR-responsive reporter genes and in HepG2 cells reduced recruitment of steroid receptor coactivator-2 by RORα at an endogenous ROR target gene (G6Pase). Using small interference RNA, we demonstrate that repression of the gluconeogenic enzyme glucose-6-phosphatase in HepG2 cells by T0901317 is ROR-dependent and is not due to the compd.'s LXR activity. In summary, T0901317 represents a novel chem. probe to examine RORα/γ function and an excellent starting point for the development of ROR selective modulators. More importantly, our results demonstrate that small mols. can be used to target the RORs for therapeutic intervention in metabolic and immune disorders.
- 181Dai, Y.-B.; Tan, X.-J.; Wu, W.-F.; Warner, M.; Gustafsson, J.-Å. Liver X Receptor β Protects Dopaminergic Neurons in a Mouse Model of Parkinson Disease. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (32), 13112– 13117, DOI: 10.1073/pnas.1210833109[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVWmsrfK&md5=07e2623bd636ee1bf6d6d65fa2a4eca7Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson diseaseDai, Yu-Bing; Tan, Xin-Jie; Wu, Wan-Fu; Warner, Margaret; Gustafsson, Jan-AkeProceedings of the National Academy of Sciences of the United States of America (2012), 109 (32), 13112-13117CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Parkinson disease (PD) is a progressive neurodegenerative disease whose progression may be slowed, but at present there is no pharmacol. intervention that would stop or reverse the disease. Liver X receptor β (LXRβ) is a member of the nuclear receptor super gene family expressed in the central nervous system, where it is important for cortical layering during development and survival of dopaminergic neurons throughout life. In the present study we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of LXRO as a target for prevention or treatment of PD. The dopaminergic neurons of the substantia nigra of LXRβ-/- mice were much more severely affected by MPTP than were those of their WT litter- mates. In addn., the no. of activated microglia and GFAP-pos. astrocytes was higher in the substantia nigra of LXRβ-/- mice than in WT littermates. Administration of the LXR agonist GW3965 to MPTP-treated WT mice protected against loss of dopa- minergic neurons and of dopaminergic fibers projecting to the striatum, and resulted in fewer activated microglia and astroglia. Surprisingly, LXRI was not expressed in the neurons of the substantia nigra but in the microglia and astroglia. We conclude that LXR agonists may have beneficial effects in treatment of PD by modulating the cytotoxic functions of microglia.
- 182Nelissen, K.; Mulder, M.; Smets, I.; Timmermans, S.; Smeets, K.; Ameloot, M.; Hendriks, J. J. A. Liver X Receptors Regulate Cholesterol Homeostasis in Oligodendrocytes. J. Neurosci. Res. 2012, 90 (1), 60– 71, DOI: 10.1002/jnr.22743[Crossref], [PubMed], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVKjsbvF&md5=d1d55372882978a9c6701863ce40536aLiver X receptors regulate cholesterol homeostasis in oligodendrocytesNelissen, Katherine; Mulder, Monique; Smets, Ilse; Timmermans, Silke; Smeets, Karen; Ameloot, Marcel; Hendriks, Jerome J. A.Journal of Neuroscience Research (2012), 90 (1), 60-71CODEN: JNREDK; ISSN:0360-4012. (Wiley-Liss, Inc.)Cholesterol synthesis and transport in oligodendrocytes are essential for optimal myelination and remyelination in pathol. conditions such as multiple sclerosis. However, little is known about cholesterol homeostasis in the myelin-forming oligodendrocytes. Liver X receptors (LXRs) are nuclear oxysterol receptors that regulate genes involved in cholesterol homeostasis and may therefore play an important role in de- and remyelination. We investigated whether LXRs regulate cholesterol homeostasis in oligodendrocytes. mRNA expression of genes encoding LXR-α and LXR-β and their target genes (ABCA1, ABCG1, ABCG4, apoE, and LDLR) was detected in oligodendrocytes derived from both neonatal and adult rats using quant. real-time PCR. The expression of LXR-β and several target genes was increased during oligodendrocyte differentiation. We further demonstrated that treatment of primary neonatal rat oligodendrocytes with the synthetic LXR agonist T0901317 induced the expression of several established LXR target genes, including ABCA1, ABCG1, apoE, and LDLR. Treatment of oligodendrocytes with T0901317 resulted in an enhanced cholesterol efflux in the presence of apolipoprotein A-I or high-d. lipoprotein particles. These data show that LXRs are involved in regulating cholesterol homeostasis in oligodendrocytes. © 2011 Wiley Periodicals, Inc.
- 183Berghoff, S. A.; Spieth, L.; Sun, T.; Hosang, L.; Schlaphoff, L.; Depp, C.; Düking, T.; Winchenbach, J.; Neuber, J.; Ewers, D.; Scholz, P.; van der Meer, F.; Cantuti-Castelvetri, L.; Sasmita, A. O.; Meschkat, M.; Ruhwedel, T.; Möbius, W.; Sankowski, R.; Prinz, M.; Huitinga, I.; Sereda, M. W.; Odoardi, F.; Ischebeck, T.; Simons, M.; Stadelmann-Nessler, C.; Edgar, J. M.; Nave, K.-A.; Saher, G. Microglia Facilitate Repair of Demyelinated Lesions via Post-Squalene Sterol Synthesis. Nat. Neurosci. 2021, 24 (1), 47– 60, DOI: 10.1038/s41593-020-00757-6[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1KktLrL&md5=6f3ea7774aa69a06d3a8f08587fe66ccMicroglia facilitate repair of demyelinated lesions via post-squalene sterol synthesisBerghoff, Stefan A.; Spieth, Lena; Sun, Ting; Hosang, Leon; Schlaphoff, Lennart; Depp, Constanze; Dueking, Tim; Winchenbach, Jan; Neuber, Jonathan; Ewers, David; Scholz, Patricia; van der Meer, Franziska; Cantuti-Castelvetri, Ludovico; Sasmita, Andrew O.; Meschkat, Martin; Ruhwedel, Torben; Moebius, Wiebke; Sankowski, Roman; Prinz, Marco; Huitinga, Inge; Sereda, Michael W.; Odoardi, Francesca; Ischebeck, Till; Simons, Mikael; Stadelmann-Nessler, Christine; Edgar, Julia M.; Nave, Klaus-Armin; Saher, GesineNature Neuroscience (2021), 24 (1), 47-60CODEN: NANEFN; ISSN:1097-6256. (Nature Research)Abstr.: The repair of inflamed, demyelinated lesions as in multiple sclerosis (MS) necessitates the clearance of cholesterol-rich myelin debris by microglia/macrophages and the switch from a pro-inflammatory to an anti-inflammatory lesion environment. Subsequently, oligodendrocytes increase cholesterol levels as a prerequisite for synthesizing new myelin membranes. We hypothesized that lesion resoln. is regulated by the fate of cholesterol from damaged myelin and oligodendroglial sterol synthesis. By integrating gene expression profiling, genetics and comprehensive phenotyping, we found that, paradoxically, sterol synthesis in myelin-phagocytosing microglia/macrophages dets. the repair of acutely demyelinated lesions. Rather than producing cholesterol, microglia/macrophages synthesized desmosterol, the immediate cholesterol precursor. Desmosterol activated liver X receptor (LXR) signaling to resolve inflammation, creating a permissive environment for oligodendrocyte differentiation. Moreover, LXR target gene products facilitated the efflux of lipid and cholesterol from lipid-laden microglia/macrophages to support remyelination by oligodendrocytes. Consequently, pharmacol. stimulation of sterol synthesis boosted the repair of demyelinated lesions, suggesting novel therapeutic strategies for myelin repair in MS.
- 184Mailleux, J.; Vanmierlo, T.; Bogie, J. F. J.; Wouters, E.; Lütjohann, D.; Hendriks, J. J. A.; van Horssen, J. Active Liver X Receptor Signaling in Phagocytes in Multiple Sclerosis Lesions. Mult. Scler. J. 2018, 24 (3), 279– 289, DOI: 10.1177/1352458517696595[Crossref], [PubMed], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvFOgtr4%253D&md5=1d65cb17f3433eb1701033621571376cActive liver X receptor signaling in phagocytes in multiple sclerosis lesionsMailleux, Jo; Vanmierlo, Tim; Bogie, Jeroen F. J.; Wouters, Elien; Lutjohann, Dieter; Hendriks, Jerome J. A.; van Horssen, JackMultiple Sclerosis Journal (2018), 24 (3), 279-289CODEN: MSJUAP; ISSN:1477-0970. (Sage Publications Ltd.)We sought to det. the liver X receptor (LXR) ligands present in human macrophages after myelin phagocytosis and whether LXRs are activated in multiple sclerosis (MS) lesions. We used real-time quant. polymerase chain reaction (PCR) and immunohistochem. to det. expression of LXRs and their response genes in human phagocytes after myelin phagocytosis and in active MS lesions. We used gas chromatog./mass spectrometric anal. to det. LXR-activating oxysterols and cholesterol precursors present and formed in myelin and myelin-incubated cells, resp. Myelin induced LXR response genes ABCA1 and ABCG1 in human monocyte-derived macrophages. In active MS lesions, we found that both gene expression and protein levels of ABCA1 and apolipoprotein E (APOE) are upregulated in foamy phagocytes. Moreover, we found that the LXR ligand 27-hydroxycholesterol (27OHC) is significantly increased in human monocyte-derived macrophages after myelin uptake. LXR response genes are upregulated in phagocytes present in active MS lesions, indicating that LXRs are activated in actively demyelinating phagocytes. In addn., we have shown that myelin contains LXR ligands and that 27OHC is generated in human monocyte-derived macrophages after myelin processing. This suggests that LXRs in phagocytes in active MS lesions are activated at least partially by (oxy)sterols present in myelin and the generation thereof during myelin processing.
- 185Cui, G.; Qin, X.; Wu, L.; Zhang, Y.; Sheng, X.; Yu, Q.; Sheng, H.; Xi, B.; Zhang, J. Z.; Zang, Y. Q. Liver X Receptor (LXR) Mediates Negative Regulation of Mouse and Human Th17 Differentiation. J. Clin. Invest. 2011, 121 (2), 658– 670, DOI: 10.1172/JCI42974[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsl2ru7c%253D&md5=dfaef076cb4e6e5b0d892c0c4d0057d8Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiationCui, Guoliang; Qin, Xia; Wu, Lili; Zhang, Yuebo; Sheng, Xiaoyan; Yu, Qiwen; Sheng, Hongguang; Xi, Beili; Zhang, Jingwu Z.; Zang, Ying QinJournal of Clinical Investigation (2011), 121 (2), 658-670CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)Th17 cells are a subset of CD4+ T cells with an important role in clearing certain bacterial and fungal pathogens. However, they have also been implicated in autoimmune diseases such as multiple sclerosis. Exposure of naive CD4+ T cells to IL-6 and TGF-β leads to Th17 cell differentiation through a process in which many proteins have been implicated. We report here that ectopic expression of liver X receptor (LXR) inhibits Th17 polarization of mouse CD4+ T cells, while LXR deficiency promotes Th17 differentiation in vitro. LXR activation in mice ameliorated disease in the exptl. autoimmune encephalomyelitis (EAE) model of multiple sclerosis, whereas LXR deficiency exacerbated disease. Further anal. revealed that Srebp-1, which is encoded by an LXR target gene, mediated the suppression of Th17 differentiation by binding to the E-box element on the Il17 promoter, phys. interacting with aryl hydrocarbon receptor (Ahr) and inhibiting Ahr-controlled Il17 transcription. The putative active site (PAS) domain of Ahr and the N-terminal acidic region of Srebp-1 were essential for this interaction. Addnl. analyses suggested that similar LXR-dependent mechanisms were operational during human Th17 differentiation in vitro. This study reports what we believe to be a novel signaling pathway underlying LXR-mediated regulation of Th17 cell differentiation and autoimmunity.
- 186Schultz, J. R.; Tu, H.; Luk, A.; Repa, J. J.; Medina, J. C.; Li, L.; Schwendner, S.; Wang, S.; Thoolen, M.; Mangelsdorf, D. J.; Lustig, K. D.; Shan, B. Role of LXRs in Control of Lipogenesis. Genes Dev. 2000, 14 (22), 2831– 2838, DOI: 10.1101/gad.850400[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXos1ehsLg%253D&md5=85a46e3313f736fe71de7c0da69f51c4Role of LXRs in control of lipogenesisSchultz, Joshua R.; Tu, Hua; Luk, Alvin; Repa, Joyce J.; Medina, Julio C.; Li, Leping; Schwendner, Susan; Wang, Shelley; Thoolen, Martin; Mangelsdorf, David J.; Lustig, Kevin D.; Shan, BeiGenes & Development (2000), 14 (22), 2831-2838CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)The discovery of oxysterols as the endogenous liver X receptor (LXR) ligands and subsequent gene targeting studies in mice provided strong evidence that LXR plays a central role in cholesterol metab. The identification here of a synthetic, nonsteroidal LXR-selective agonist series represented by T0314407 and T0901317 revealed a novel physiol. role of LXR. Oral administration of T0901317 to mice and hamsters showed that LXR activated the coordinate expression of major fatty acid biosynthetic genes (lipogenesis) and increased plasma triglyceride and phospholipid levels in both species. Complementary studies in cell culture and animals suggested that the increase in plasma lipids occurs via LXR-mediated induction of the sterol regulatory element-binding protein 1 (SREBP-1) lipogenic program.
- 187Collins, J. L.; Fivush, A. M.; Watson, M. A.; Galardi, C. M.; Lewis, M. C.; Moore, L. B.; Parks, D. J.; Wilson, J. G.; Tippin, T. K.; Binz, J. G.; Plunket, K. D.; Morgan, D. G.; Beaudet, E. J.; Whitney, K. D.; Kliewer, S. A.; Willson, T. M. Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary Amines. J. Med. Chem. 2002, 45 (10), 1963– 1966, DOI: 10.1021/jm0255116[ACS Full Text], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XivVOmu7w%253D&md5=296ce6aa3e3a49275b74d6b94b7304e8Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary AminesCollins, Jon L.; Fivush, Adam M.; Watson, Michael A.; Galardi, Cristin M.; Lewis, Michael C.; Moore, Linda B.; Parks, Derek J.; Wilson, Joan G.; Tippin, Tim K.; Binz, Jane G.; Plunket, Kelli D.; Morgan, Daniel G.; Beaudet, Elizabeth J.; Whitney, Karl D.; Kliewer, Steven A.; Willson, Timothy M.Journal of Medicinal Chemistry (2002), 45 (10), 1963-1966CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A potent, selective, orally active liver x receptor (LXR) agonist was identified from focused libraries of tertiary amines. GW3965 recruits the steroid receptor coactivator 1 to human LXRα in a cell-free ligand-sensing assay with an EC50 of 125 nM and profiles as a full agonist on hLXRα and hLXRβ in cell-based reporter gene assays with EC50's of 190 and 30 nM, resp. After oral dosing at 10 mg/kg to C57BL/6 mice, GW3965 increased expression of the reverse cholesterol transporter ABCA1 in the small intestine and peripheral macrophages and increased the plasma concns. of HDL cholesterol by 30%. GW3965 will be a valuable chem. tool to investigate the role of LXR in the regulation of reverse cholesterol transport and lipid metab.
- 188Kirchgessner, T. G.; Martin, R.; Sleph, P.; Grimm, D.; Liu, X.; Lupisella, J.; Smalley, J.; Narayanan, R.; Xie, Y.; Ostrowski, J.; Cantor, G. H.; Mohan, R.; Kick, E. Pharmacological Characterization of a Novel Liver X Receptor Agonist with Partial LXRα Activity and a Favorable Window in Nonhuman Primates. J. Pharmacol. Exp. Ther. 2015, 352 (2), 305– 314, DOI: 10.1124/jpet.114.219923[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFSqtb8%253D&md5=cc48fcf571e48e8f1ff417896b6d9ad0Pharmacological characterization of a novel liver X receptor agonist with partial LXRα activity and a favorable window in nonhuman primatesKirchgessner, Todd G.; Martin, Richard; Sleph, Paul; Grimm, Denise; Liu, Xiaoqin; Lupisella, John; Smalley, James; Narayanan, Rangaraj; Xie, Yinong; Ostrowski, Jacek; Cantor, Glenn H.; Mohan, Raju; Kick, EllenJournal of Pharmacology and Experimental Therapeutics (2015), 352 (2), 305-314/1-305-314/10, 10 pp.CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Liver X Receptors (LXRs) α and β are nuclear hormone receptors that regulate multiple genes involved in reverse cholesterol transport (RCT) and are potential drug targets for atherosclerosis. However, full pan agonists also activate lipogenic genes, resulting in elevated plasma and hepatic lipids. We report the pharmacol. of BMS-779788 [2-(2-(1-(2-chlorophenyl)-1-methylethyl)-1- (39-(methylsulfonyl)-4-biphenylyl)-1H-imidazol-4-yl)-2-propanol], a potent partial LXR agonist with LXRβ selectivity, which has an improved therapeutic window in the cynomolgus monkey compared with a full pan agonist. BMS-779788 induced LXR target genes in blood in vivo with an EC505610 nM, a value similar to its in vitro blood gene induction potency. BMS-779788 was 29- and 12-fold less potent than the full agonist T0901317 in elevating plasma triglyceride and LDL cholesterol, resp., with similar results for plasma cholesteryl ester transfer protein and apolipoprotein B. However, ABCA1 and ABCG1 mRNA inductions in blood, which are crit. for RCT,were comparable. Increased liver triglyceride was obsd. after 7-day treatment with BMS-779788 at the highest dose tested and was nearly identical to the dose response for plasma triglyceride, consistent with the central role of liver LXR in these lipogenic effects. Dose-dependent increases in biliary cholesterol and decreases in phospholipid and bile acid occurred in BMS-779788-treated animals, similar to LXR agonist effects reported in mouse. In summary, BMS- 779788, a partial LXRβ selective agonist, has decreased lipogenic potential compared with a full pan agonist in cynomolgus monkeys, with similar potency in the induction of genes known to stimulate RCT. This provides support in nonhuman primates for improving LXR agonist therapeutic windows by limiting LXRα activity.
- 189Wrobel, J.; Steffan, R.; Bowen, S. M.; Magolda, R.; Matelan, E.; Unwalla, R.; Basso, M.; Clerin, V.; Gardell, S. J.; Nambi, P.; Quinet, E.; Reminick, J. I.; Vlasuk, G. P.; Wang, S.; Feingold, I.; Huselton, C.; Bonn, T.; Farnegardh, M.; Hansson, T.; Nilsson, A. G.; Wilhelmsson, A.; Zamaratski, E.; Evans, M. J. Indazole-Based Liver X Receptor (LXR) Modulators with Maintained Atherosclerotic Lesion Reduction Activity but Diminished Stimulation of Hepatic Triglyceride Synthesis. J. Med. Chem. 2008, 51 (22), 7161– 7168, DOI: 10.1021/jm800799q[ACS Full Text], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlWqur7J&md5=8a9e70594fc1f4f3c32bc2e3cd040248Indazole-Based Liver X Receptor (LXR) Modulators with Maintained Atherosclerotic Lesion Reduction Activity but Diminished Stimulation of Hepatic Triglyceride SynthesisWrobel, Jay; Steffan, Robert; Bowen, S. Marc; Magolda, Ronald; Matelan, Edward; Unwalla, Rayomand; Basso, Michael; Clerin, Valerie; Gardell, Stephen J.; Nambi, Ponnal; Quinet, Elaine; Reminick, Jason I.; Vlasuk, George P.; Wang, Shuguang; Feingold, Irene; Huselton, Christine; Bonn, Tomas; Farnegardh, Mathias; Hansson, Tomas; Nilsson, Annika Goos; Wilhelmsson, Anna; Zamaratski, Edouard; Evans, Mark J.Journal of Medicinal Chemistry (2008), 51 (22), 7161-7168CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepd. as LXR modulators. These compds. were partial agonists in transactivation assays when compared to T0901317 and were slightly weaker with respect to potency and efficacy on LXRα than on LXRβ. Lead compds. in this series WAY-252623 (I) and WAY-214950 (II) showed less lipid accumulation in HepG2 cells than potent full agonists T0901317 and WAY-254011, but were comparable in efficacy to T0901317 and WAY-254011 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. WAY-214950 reduced aortic lesion area in LDLR knockout mice equivalently to WAY-254011, or pos. control GW3965. In a 7-day hamster model, WAY-214950 showed a lesser propensity for plasma TG elevation than WAY-254011,, when the compds. were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for GW3965, the lack of TG effect of WAY-214950 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by WAY-254011. These results suggest indazoles such as WAY-214950 may have an improved profile for potential use as a therapeutic agent.
- 190Stachel, S. J.; Zerbinatti, C.; Rudd, M. T.; Cosden, M.; Suon, S.; Nanda, K. K.; Wessner, K.; Dimuzio, J.; Maxwell, J.; Wu, Z.; Uslaner, J. M.; Michener, M. S.; Szczerba, P.; Brnardic, E.; Rada, V.; Kim, Y.; Meissner, R.; Wuelfing, P.; Yuan, Y.; Ballard, J.; Holahan, M.; Klein, D. J.; Lu, J.; Fradera, X.; Parthasarathy, G.; Uebele, V. N.; Chen, Z.; Li, Y.; Li, J.; Cooke, A. J.; Bennett, D. J.; Bilodeau, M. T.; Renger, J. Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease. J. Med. Chem. 2016, 59 (7), 3489– 3498, DOI: 10.1021/acs.jmedchem.6b00176[ACS Full Text], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XkvVaht7k%253D&md5=17ebde13cff428dffe1b7ef70944ee28Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer's DiseaseStachel, Shawn J.; Zerbinatti, Celina; Rudd, Michael T.; Cosden, Mali; Suon, Sokreine; Nanda, Kausik K.; Wessner, Keith; DiMuzio, Jillian; Maxwell, Jill; Wu, Zhenhua; Uslaner, Jason M.; Michener, Maria S.; Szczerba, Peter; Brnardic, Edward; Rada, Vanessa; Kim, Yuntae; Meissner, Robert; Wuelfing, Peter; Yuan, Yang; Ballard, Jeanine; Holahan, Marie; Klein, Daniel J.; Lu, Jun; Fradera, Xavier; Parthasarathy, Gopal; Uebele, Victor N.; Chen, Zhongguo; Li, Yingjie; Li, Jian; Cooke, Andrew J.; Bennett, D. Jonathan; Bilodeau, Mark T.; Renger, JohnJournal of Medicinal Chemistry (2016), 59 (7), 3489-3498CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, soly., and phys. properties to allow efficacy and safety studies in vivo. Compd. 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.
- 191Gezen-Ak, D.; Dursun, E. Molecular Basis of Vitamin D Action in Neurodegeneration: The Story of a Team Perspective. Hormones 2019, 18 (3), 17– 21, DOI: 10.1007/s42000-018-0087-4[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3crlsFGksg%253D%253D&md5=922bd4c7bc56fb90646b6d16e9882e78Molecular basis of vitamin D action in neurodegeneration: the story of a team perspectiveGezen-Ak Duygu; Dursun ErdincHormones (Athens, Greece) (2019), 18 (1), 17-21 ISSN:.Vitamin D, a secosteroid hormone, has, over the years, mainly been known for its classic role in the maintenance of calcium homeostasis of the human body. However, there is increasing understanding that vitamin D contributes to the regulation of Ca(2+) homeostasis, especially via voltage-gated calcium channels, in another major organ that uses calcium, the brain. Almost 30 years ago, the role of dysregulation in the aging brain and in Alzheimer's disease (AD) gave rise to the Ca(2+) hypothesis of brain aging and dementia. We thus made calcium homeostasis the starting point of our studies, proposing the notion that the consequences of long-term deficiency and/or inefficient utilization of vitamin D may cause the disruption of calcium homeostasis in neurons, this creating a vulnerability of neurons to aging and neurodegeneration. In this mini-review, we aim to describe the potential of vitamin D (cholecalciferol) as a neurosteroid based on our findings and conclusions.
- 192Makishima, M.; Lu, T. T.; Xie, W.; Whitfield, G. K.; Domoto, H.; Evans, R. M.; Haussler, M. R.; Mangelsdorf, D. J. Vitamin D Receptor as an Intestinal Bile Acid Sensor. Science 2002, 296 (5571), 1313– 1316, DOI: 10.1126/science.1070477[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xjsl2qur0%253D&md5=39a9632c4acad961660105bf4121bde0Vitamin D receptor as an intestinal bile acid sensorMakishima, Makoto; Lu, Timothy T.; Xie, Wen; Whitfield, G. Kerr; Domoto, Hideharu; Evans, Ronald M.; Haussler, Mark R.; Mangelsdorf, David J.Science (Washington, DC, United States) (2002), 296 (5571), 1313-1316CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The authors show that VDR also functions as a receptor for the secondary bile acid lithocholic acid (LCA), which is hepatotoxic and a potential enteric carcinogen. VDR is an order of magnitude more sensitive to LCA and its metabolites than are other nuclear receptors. Activation of VDR by LCA or vitamin D induced expression in vivo of CYP3A, a cytochrome P 450 enzyme that detoxifies LCA in the liver and intestine. These studies offer a mechanism that may explain the proposed protective effects of vitamin D and its receptor against colon cancer.
- 193Yao, B.; He, J.; Yin, X.; Shi, Y.; Wan, J.; Tian, Z. The Protective Effect of Lithocholic Acid on the Intestinal Epithelial Barrier Is Mediated by the Vitamin D Receptor via a SIRT1/Nrf2 and NF-KB Dependent Mechanism in Caco-2 Cells. Toxicol. Lett. 2019, 316, 109– 118, DOI: 10.1016/j.toxlet.2019.08.024[Crossref], [PubMed], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVSqsrzF&md5=c08df1d014dbf00b083c41a937bf5838The protective effect of lithocholic acid on the intestinal epithelial barrier is mediated by the vitamin D receptor via a SIRT1/Nrf2 and NF-κB dependent mechanism in Caco-2 cellsYao, Baiyu; He, Jingni; Yin, Xin; Shi, Yang; Wan, Jun; Tian, ZhongToxicology Letters (2019), 316 (), 109-118CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Lithocholic acid (LCA) is both a secondary bile acid and a vitamin D receptor (VDR) ligand. The VDR is activated by 1,25-dihydroxy vitamin D3 and plays an important role in maintaining integrity of the intestinal mucosal barrier. LCA can also substitute for vitamin D to carry out the in vivo functions of vitamin D. However, it is unclear whether activation of the VDR by LCA affects mucosal barrier function. In the present study, the authors researched the protective effect of LCA on tumor necrosis factor-alpha (TNF-α)-induced intestinal epithelial barrier dysfunction in Caco-2 cells of the human epithelial intestinal adenocarcinoma cell line. Caco-2 cell monolayers were pretreated with LCA and then exposed to 100 ng/mL TNF-α. The results showed that LCA alleviated the decrease in transepithelial elec. resistance and the increase in FITC-Dextran flux induced by TNF-α. LCA ameliorated the TNF-α-induced decrease in protein expression and distribution of ZO-1, E-cadherin, Occludin, and Claudin-1, which are tight junction markers. Addnl., the LCA treatment effectively counteracted TNF-α-mediated downregulation of silent information regulator 1 (SIRT1), nuclear factor erythroid-2-related factor 2 (Nrf2), and heme oxygenase-1, which are related to oxidative stress. Increases in NF-κB p-p65 and p-IκB-α induced by TNF-α were significantly inhibited by LCA. Considering all these, the present study indicates that LCA has a significant protective effect on TNF-α-induced injury of intestinal barrier function through the VDR and suggests that suppressing NF-κB signaling and activating the SIRT1/Nrf2 pathway might be one of the mechanisms underlying the protective effect of LCA.
- 194Eyles, D. W.; Smith, S.; Kinobe, R.; Hewison, M.; McGrath, J. J. Distribution of the Vitamin D Receptor and 1α-Hydroxylase in Human Brain. J. Chem. Neuroanat. 2005, 29 (1), 21– 30, DOI: 10.1016/j.jchemneu.2004.08.006[Crossref], [PubMed], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVKktrrI&md5=f1117120c82d61138b44eed5b4dce0d7Distribution of the vitamin D receptor and 1α-hydroxylase in human brainEyles, Darryl W.; Smith, Steven; Kinobe, Robert; Hewison, Martin; McGrath, John J.Journal of Chemical Neuroanatomy (2005), 29 (1), 21-30CODEN: JCNAEE; ISSN:0891-0618. (Elsevier B.V.)Despite a growing body of evidence that Vitamin D is involved in mammalian brain functioning, there has been a lack of direct evidence about its role in the human brain. This paper reports, for the first time, the distribution of the 1,25-dihydroxyvitamin D3 receptor (VDR), and 1α-hydroxylase (1α-OHase), the enzyme responsible for the formation of the active vitamin in the human brain. The receptor and the enzyme were found in both neurons and glial cells in a regional and layer-specific pattern. The VDR was restricted to the nucleus while 1α-OHase was distributed throughout the cytoplasm. The distribution of the VDR in human brain was strikingly similar to that reported in rodents. Many regions contained equiv. amts. of both the VDR and 1α-OHase, however the macrocellular cells within the nucleus basalis of Meynert (NBM) and the Purkinje cells in the cerebellum expressed 1α-OHase in the absence of VDR. The strongest immunohistochem. staining for both the receptor and enzyme was in the hypothalamus and in the large (presumably dopaminergic) neurons within the substantia nigra. The obsd. distribution of the VDR is consistent with the proposal that Vitamin D operates in a similar fashion to the known neurosteroids. The widespread distribution of 1α-OHase and the VDR suggests that Vitamin D may have autocrine/paracrine properties in the human brain.
- 195Burne, T. H. J.; McGrath, J. J.; Eyles, D. W.; Mackay-Sim, A. Behavioural Characterization of Vitamin D Receptor Knockout Mice. Behav. Brain Res. 2005, 157 (2), 299– 308, DOI: 10.1016/j.bbr.2004.07.008[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXisl2ntA%253D%253D&md5=e1f749cdaf7fc87f63411903b246d5beBehavioural characterization of Vitamin D receptor knockout miceBurne, Thomas H. J.; McGrath, John J.; Eyles, Darryl W.; Mackay-Sim, AlanBehavioural Brain Research (2005), 157 (2), 299-308CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)Vitamin D (calcitriol) is a nuclear transcription regulator acting via a nuclear hormone receptor (VDR). In addn. to its role in the regulation of calcium and phosphate homeostasis and in bone formation, Vitamin D is also thought to be involved in brain function. The aim of this study was to behaviorally phenotype VDR knockout mice. We characterized the behavior of VDR null mutant mice and wildtype littermate controls by subjecting them to a range of tests including a primary behavioral screen (using the SHIRPA protocol), rotarod, gait anal., Y-maze, marble burying test, bedding test, holeboard test, elevated plus maze, open field test and prepulse inhibition of the acoustic startle response. There were no effects of genotype on most of the scores from the SHIRPA protocol except that VDR -/- mice had alopecia, were shorter and weighed less than VDR +/+ mice. VDR -/- mice had a shorter gait as well as impairments on the rotarod, in the bedding test and impaired habituation in both the open field and on the acoustic startle response. The VDR -/- mice had normal acoustic startle responses but had impaired PPI at long (256 ms) but not short (64 ms) prepulse to pulse intervals. The VDR -/- mice were less active in the open field and buried fewer marbles in the marble burying test. However, there were no differences in the time spent on the open arms of the elevated plus maze or in working memory as assessed by repeat arm entries on the Y-maze. Therefore, it appears that VDR -/- mice have muscular and motor impairments that significantly affects locomotor behavior but seemingly no impairments in cognition as indicated by exploration, working memory or anxiety.
- 196Beecham, G. W.; Martin, E. R.; Li, Y. J.; Slifer, M. A.; Gilbert, J. R.; Haines, J. L.; Pericak-Vance, M. A. Genome-Wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease. Am. J. Hum. Genet. 2009, 84 (1), 35– 43, DOI: 10.1016/j.ajhg.2008.12.008[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpsFakug%253D%253D&md5=3921f86f883e036ef5fae49c45f8ea79Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer diseaseBeecham, Gary W.; Martin, Eden R.; Li, Yi-Ju; Slifer, Michael A.; Gilbert, John R.; Haines, Jonathan L.; Pericak-Vance, Margaret A.American Journal of Human Genetics (2009), 84 (1), 35-43CODEN: AJHGAG; ISSN:0002-9297. (Cell Press)Only Apolipoprotein E polymorphisms have been consistently assocd. with the risk of late-onset Alzheimer disease (LOAD), but they represent only a minority of the underlying genetic effect. To identify addnl. LOAD risk loci, we performed a genome-wide assocn. study (GWAS) on 492 LOAD cases and 498 cognitive controls using Illumina's HumanHap550 beadchip. An addnl. 238 cases and 220 controls were used as a validation data set for single-nucleotide polymorphisms (SNPs) that met genome-wide significance. To validate addnl. assocd. SNPs and nominally assocd. candidate genes, we imputed SNPs from our GWAS using a previously published LOAD GWAS1 and the IMPUTE program. Assocn. testing was performed with the Cochran-Armitage trend test and logistic regression, and genome-wide significance was detd. with the False Discovery Rate-Beta Uniform Mixt. method. Extensive quality-control methods were performed at both the sample and the SNP level. The GWAS confirmed the known APOE assocn. and identified assocn. with a 12q13 locus at genome-wide significance; the 12q13 locus was confirmed in our validation data set. Four addnl. highly assocd. signals (1q42, 4q28, 6q14, 19q13) were replicated with the use of the imputed data set, and six candidate genes had SNPs with nominal assocn. in both the GWAS and the joint imputated data set. These results help to further define the genetic architecture of LOAD.
- 197Butler, M. W.; Burt, A.; Edwards, T. L.; Zuchner, S.; Scott, W. K.; Martin, E. R.; Vance, J. M.; Wang, L. Vitamin D Receptor Gene as a Candidate Gene for Parkinson Disease. Ann. Hum. Genet. 2011, 75 (2), 201– 210, DOI: 10.1111/j.1469-1809.2010.00631.x[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjvFOgtbo%253D&md5=8e97d45c5e8eb65878abe41af5b08fa7Vitamin D receptor gene as a candidate gene for Parkinson diseaseButler, Megan W.; Burt, Amber; Edwards, Todd L.; Zuchner, Stephan; Scott, William K.; Martin, Eden R.; Vance, Jeffery M.; Wang, LiyongAnnals of Human Genetics (2011), 75 (2), 201-210CODEN: ANHGAA; ISSN:0003-4800. (Wiley-Blackwell)Vitamin D and vitamin D receptor (VDR) have been postulated as environmental and genetic factors in neurodegeneration disorders including multiple sclerosis (MS), Alzheimer disease (AD), and recently Parkinson disease (PD). Given the sparse data on PD, we conducted a two-stage study to evaluate the genetic effects of VDR in PD. In the discovery stage, 30 tagSNPs in VDR were tested for assocn. with risk as a discrete trait and age-at-onset (AAO) as a quant. trait in 770 Caucasian PD families. In the validation stage, 18 VDR SNPs were tested in an independent Caucasian cohort (267 cases and 267 controls) constructed from a genome-wide assocn. study (GWAS). In the discovery dataset, SNPs in the 5' end of VDR were assocd. with both risk and AAO with more significant evidence of assocn. with AAO (P = 0.0008-0.02). These 5' SNPs were also assocd. with AD in another study. In the validation dataset, SNPs in the 3' end of VDR were assocd. with AAO (P = 0.003) but not risk. The 3' end SNP has been assocd. with both MS and AD in previous studies. Our findings suggest VDR as a potential susceptibility gene and support an essential role of vitamin D in PD.
- 198Kim, J.-S.; Kim, Y.-I.; Song, C.; Yoon, I.; Park, J.-W.; Choi, Y.-B.; Kim, H.-T.; Lee, K.-S. Association of Vitamin D Receptor Gene Polymorphism and Parkinson’s Disease in Koreans. J. Korean Med. Sci. 2005, 20 (3), 495– 498, DOI: 10.3346/jkms.2005.20.3.495[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXms1eiurY%253D&md5=bd63d3d4a6729edfe07e07ebab85f3b1Association of vitamin D receptor gene polymorphism and parkinson's disease in KoreansKim, Joong-Seok; Kim, Yeong-In; Song, Christopher; Yoon, Injin; Park, Jeong-Wook; Choi, Young-Bin; Kim, Hee-Tae; Lee, Kwang-SooJournal of Korean Medical Science (2005), 20 (3), 495-498CODEN: JKMSEH; ISSN:1011-8934. (Korean Academy of Medical Science)1 α,25-Dihydroxyvitamin D3 (1,25(OH)2D3), which is the biol. active form of vitamin D, has anti-inflammatory effects and can prevent exptl. Parkinson's disease (PD). 1,25(OH)2D3 exerts most of its actions only after it binds to its specific nuclear receptors. Eighty-five Korean patients with PD and 231 unrelated healthy individuals were evaluated to det. if vitamin D receptor gene (VDRG) Bsml polymorphisms were markers for the susceptibility to PD in Korean patients. Each polymorphism was detected using polymerase chain reaction (PCR)-based restriction anal. In addn., the relationship between the Bsml polymorphisms and the clin. manifestations of PD was evaluated. Overexpression of the b allele (91.2 vs. 85.7%; p=0.069) and homozygote bb (84.7 vs. 72.7%; p=0.043) was found in the PD patients compared with the controls. These results show for the first time an assocn. between PD and a VDRG polymorphism, which might be involved in the pathogenesis of PD, or in the linkage disequil. of the VDRG to another pathogenic gene locus.
- 199Niino, M.; Miyazaki, Y. Genetic Polymorphisms Related to Vitamin D and the Therapeutic Potential of Vitamin D in Multiple Sclerosis. Can. J. Physiol. Pharmacol. 2015, 93 (5), 319– 325, DOI: 10.1139/cjpp-2014-0374[Crossref], [PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltVSis74%253D&md5=ca1410da20829884650b88cabdaa6f7eGenetic polymorphisms related to vitamin D and the therapeutic potential of vitamin D in multiple sclerosis1Niino, Masaaki; Miyazaki, YuseiCanadian Journal of Physiology and Pharmacology (2015), 93 (5), 319-325CODEN: CJPPA3; ISSN:0008-4212. (Canadian Science Publishing)Vitamin D receptors (VDRs), which are responsible for most vitamin D functions, are expressed on various immune cells. Vitamin D is considered to be a potent immunomodulator. A variety of cells in the central nervous system (CNS) also express VDRs; thus, vitamin D may play a role in the regulation of neurodegeneration and repair processes within the CNS. Considered together with epidemiol. studies, low vitamin D status is reckoned to be one of the risk factors for multiple sclerosis (MS). Further, vitamin D is considered to be a possible treatment for MS. However, previous clin. trials with small cohorts have not demonstrated significant effects of vitamin D in MS. Current ongoing clin. trials with large cohorts could provide answers with respect to the clin. effects of vitamin D in MS. However, genetic studies have suggested that genes assocd. with vitamin D, including VDRs, are susceptible genes for MS. Vitamin D needs to be considered from the perspective of the interaction between vitamin-D-related genetic factors and environmental factors affecting vitamin D levels.
- 200Vinh quôc Luong, K.; Thi Hoàng Nguyên, L. Vitamin D and Parkinson’s Disease. J. Neurosci Res. 2012, 90, 2227– 2236, DOI: 10.1002/jnr.23115[Crossref], [PubMed], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bitFWhug%253D%253D&md5=df1252abf63c4dfa79271195cc633a71Vitamin D and Parkinson's diseaseVinh Quoc Luong Khanh; Thi Hoang Nguyen LanJournal of neuroscience research (2012), 90 (12), 2227-36 ISSN:.Parkinson's disease (PD) is the second most common form of neurodegeneration among the elderly population. PD is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. Interestingly, a significant association has been demonstrated between PD and low levels of vitamin D in the serum, and vitamin D supplement appears to have a beneficial clinical effect on PD. Genetic studies have provided the opportunity to determine which proteins link vitamin D to PD pathology, e.g., Nurr1 gene, toll-like receptor, gene related to lipid disorders, vascular endothelial factor, tyrosine hydroxylase, and angiogenin. Vitamin D also exerts its effects on cancer through nongenomic factors, e.g., bacillus Calmette-Guerin vaccination, interleukin-10, Wntβ-catenin signaling pathways, mitogen-activated protein kinase pathways, and the reduced form of the nicotinamide adenine dinucleotide phosphate. In conclusion, vitamin D might have a beneficial role in PD. Calcitriol is best used for PD because it is the active form of the vitamin D(3) metabolite and modulates inflammatory cytokine expression. Further investigation with calcitriol in PD is needed.
- 201Banerjee, A.; Khemka, V. K.; Ganguly, A.; Roy, D.; Ganguly, U.; Chakrabarti, S. Vitamin D and Alzheimer’s Disease: Neurocognition to Therapeutics. Int. J. Alzheimer's Dis. 2015, 2015, 192747, DOI: 10.1155/2015/192747[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC283gs12jsQ%253D%253D&md5=a367406ad5891beb4a343b2bdb58ad06Vitamin D and Alzheimer's Disease: Neurocognition to TherapeuticsBanerjee Anindita; Khemka Vineet Kumar; Ganguly Anirban; Roy Debashree; Ganguly Upasana; Chakrabarti SasankaInternational journal of Alzheimer's disease (2015), 2015 (), 192747 ISSN:2090-8024.Alzheimer's disease (AD), the major cause of dementia worldwide, is characterized by progressive loss of memory and cognition. The sporadic form of AD accounts for nearly 90% of the patients developing this disease. The last century has witnessed significant research to identify various mechanisms and risk factors contributing to the complex etiopathogenesis of AD by analyzing postmortem AD brains and experimenting with animal and cell culture based models. However, the treatment strategies, as of now, are only symptomatic. Accumulating evidences suggested a significant association between vitamin D deficiency, dementia, and AD. This review encompasses the beneficial role of vitamin D in neurocognition and optimal brain health along with epidemiological evidence of the high prevalence of hypovitaminosis D among aged and AD population. Moreover, disrupted signaling, altered utilization of vitamin D, and polymorphisms of several related genes including vitamin D receptor (VDR) also predispose to AD or AD-like neurodegeneration. This review explores the relationship between this gene-environmental influence and long term vitamin D deficiency as a risk factor for development of sporadic AD along with the role and rationale of therapeutic trials with vitamin D. It is, therefore, urgently warranted to further establish the role of this potentially neuroprotective vitamin in preventing and halting progressive neurodegeneration in AD patients.
- 202Luong, K.; Nguyen, L. Role of Vitamin D in Parkinson’s Disease. ISRN Neurol. 2012, 2012, 134289 DOI: 10.5402/2012/134289
- 203Munger, K. L.; Levin, L. I.; Hollis, B. W.; Howard, N. S.; Ascherio, A. Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis. J. Am. Med. Assoc. 2006, 296 (23), 2832– 2838, DOI: 10.1001/jama.296.23.2832[Crossref], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtlCqtL3J&md5=af7a4ba3d8bb7d69375933655f575179Serum 25-hydroxyvitamin D levels and risk of multiple sclerosisMunger, Kassandra L.; Levin, Lynn I.; Hollis, Bruce W.; Howard, Noel S.; Ascherio, AlbertoJAMA, the Journal of the American Medical Association (2006), 296 (23), 2832-2838CODEN: JAMAAP; ISSN:0098-7484. (American Medical Association)Context Epidemiol. and exptl. evidence suggests that high levels of vitamin D, a potent immuno-modulator, may decrease the risk of multiple sclerosis. There are no prospective studies addressing this hypothesis. Objective To examine whether levels of 25-hydroxyvitamin D are assocd. with risk of multiple sclerosis. Design, Setting, and Participants Prospective, nested case-control study among more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. Multiple sclerosis cases were identified through Army and Navy phys. disability databases for 1992 through 2004, and diagnoses were confirmed by medical record review. Each case (n = 257) was matched to 2 controls by age, sex, race/ethnicity, and dates of blood collection. Vitamin D status was estd. by averaging 25-hydroxyvitamin D levels of 2 or more serum samples collected before the date of initial multiple sclerosis symptoms. Main Outcome Measures Odds ratios of multiple sclerosis assocd. with continuous or categorical levels (quantiles or a priori-defined categories) of serum 25-hydroxyvitamin D within each racial/ethnic group. Results Among whites (148 cases, 296 controls), the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D (odds ratio [OR] for a 50-nmol/L increase in 25-hydroxyvitamin D, 0.59; 95% confidence interval, 0.36-0.97). In categorical analyses using the lowest quintile (<63.3 nmol/L) as the ref., the ORs for each subsequent quintile were 0.57, 0.57, 0.74, and 0.38 (P =.02 for trend across quintiles). Only the OR for the highest quintile, corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L, was significantly different from 1.00 (OR, 0.38; 95% confidence interval, 0.19-0.75; P =.006). The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years. Among blacks and Hispanics (109 cases, 218 controls), who had lower 25-hydroxyvitamin D levels than whites, no significant assocns. between vitamin D and multiple sclerosis risk were found. Conclusion The results of our study suggest that high circulating levels of vitamin D are assocd. with a lower risk of multiple sclerosis.
- 204Moretti, R.; Morelli, M. E.; Caruso, P. Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact. Int. J. Mol. Sci. 2018, 19 (8), 2245, DOI: 10.3390/ijms19082245[Crossref], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXns1Wju7o%253D&md5=7c20b0c642d3fb41bd1b5785093be3dcVitamin D in neurological diseases: a rationale for a pathogenic impactMoretti, Rita; Morelli, Maria Elisa; Caruso, PaolaInternational Journal of Molecular Sciences (2018), 19 (8), 2245/1-2245/27CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. It is widely known that vitamin D receptors have been found in neurons and glial cells, and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical gray nuclei, and substantia nigra. Vitamin D helps the regulation of neurotrophin, neural differentiation, and maturation, through the control operation of growing factors synthesis (i.e., neural growth factor [NGF] and glial cell line-derived growth factor (GDNF), the trafficking of the septohippocampal pathway, and the control of the synthesis process of different neuromodulators (such as acetylcholine [Ach], dopamine [DA], and gamma-aminobutyric [GABA]). Based on these assumptions, we have written this review to summarize the potential role of vitamin D in neurol. pathologies. This work could be titanic and the results might have been very fuzzy and even incoherent had we not conjectured to taper our first intentions and devoted our interests towards three mainstreams, demyelinating pathologies, vascular syndromes, and neurodegeneration. As a result of the lack of useful therapeutic options, apart from the disease-modifying strategies, the role of different risk factors should be investigated in neurol., as their correction may lead to the improvement of the cerebral conditions. We have explored the relationships between the gene-environmental influence and long-term vitamin D deficiency, as a risk factor for the development of different types of neurol. disorders, along with the role and the rationale of therapeutic trials with vitamin D implementation.
- 205Salzer, J.; Hallmans, G.; Nyström, M.; Stenlund, H.; Wadell, G.; Sundström, P. Vitamin D as a Protective Factor in Multiple Sclerosis. Neurology 2012, 79 (21), 2140– 2145, DOI: 10.1212/WNL.0b013e3182752ea8[Crossref], [PubMed], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslaitbrN&md5=accb50f9e6299dc50dae9298bd4720a3Vitamin D as a protective factor in multiple sclerosisSalzer, Jonatan; Hallmans, Goeran; Nystroem, Maria; Stenlund, Hans; Wadell, Goeran; Sundstroem, PeterNeurology (2012), 79 (21), 2140-2145CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: To examine the assocn. between 25-hydroxyvitamin D (25[OH]D) levels and the risk of multiple sclerosis (MS) in blood samples collected prospectively and during gestation. Methods: In this nested case-control study, 2 population-based biobanks with 291,500 samples from 164,000 persons collected since 1975 in the northern half of Sweden were used. We identified prospectively collected blood samples from MS cases (n = 192, controls matched 2:1) and gestational samples from pregnant mothers where the offspring had later developed MS (n = 37, control mothers matched 5:1). 25(OH)D levels were measured using an ELISA, and the risk of MS was analyzed using matched logistic regression. Results: Levels of 25(OH)D ≥75 (vs <75) nmol/L in prospectively collected blood samples were assocd. with a decreased risk of MS (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.16-0.98). No decrease in MS risk was found in the offspring exposed to gestational 25(OH)D levels ≥75 (vs <75) nmol/L (OR 1.8, 95% CI 0.53-5.8). The prevalence of 25(OH)D levels ≥75 nmol/L in female controls decreased gradually during 1976-2005 (p trend = 0.005). Conclusion: This study supports the presence of an assocn. between high 25(OH)D levels during the years preceding disease onset and a decreased risk of MS. In the very limited material with samples drawn in early pregnancy, where month-of-birth effects were controlled for, we found no assocn. between gestational 25(OH)D levels and MS risk in the offspring. Decreasing 25(OH)D levels in the population may contribute to explain the increasing MS incidence that is suggested from epidemiol. studies.
- 206Grimm, M. O. W.; Lauer, A. A.; Grösgen, S.; Thiel, A.; Lehmann, J.; Winkler, J.; Janitschke, D.; Herr, C.; Beisswenger, C.; Bals, R.; Grimm, H. S.; Hartmann, T. Profiling of Alzheimer’s Disease Related Genes in Mild to Moderate Vitamin D Hypovitaminosis. J. Nutr. Biochem. 2019, 67, 123– 137, DOI: 10.1016/j.jnutbio.2019.01.015[Crossref], [PubMed], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXltFGgtbc%253D&md5=de88609a5533e6d95e9d87122cde0e4fProfiling of Alzheimer's disease related genes in mild to moderate vitamin D hypovitaminosisGrimm, Marcus O. W.; Lauer, Anna A.; Groesgen, Sven; Thiel, Andrea; Lehmann, Johannes; Winkler, Jakob; Janitschke, Daniel; Herr, Christian; Beisswenger, Christoph; Bals, Robert; Grimm, Heike S.; Hartmann, TobiasJournal of Nutritional Biochemistry (2019), 67 (), 123-137CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)A vast majority of the elderly population shows a mild to moderate vitamin D deficiency. Besides the well-known function of vitamin D, vitamin D receptor is also expressed in brain and is discussed to regulate several genes. However very little is known whether genes are regulated, assocd. with Alzheimer's disease (AD). Here we investigate 117 genes, known to be affected in AD, in mouse brain samples with a mild vitamin D hypovitaminosis comparable to the vitamin D status of the elderly population (20%-30% deficiency). The 117 genes include two pos. controls, Nep and Park7, already known to be affected by both AD and vitamin D hypovitaminosis. The 25 most promising candidates were verified in a second independent mouse cohort, resulting in eleven genes further evaluated against three addnl. housekeeping genes. Three of the remaining eight significantly altered genes are involved in APP homeostasis (Snca, Nep, Psmb5), and each one gene in oxidative stress (Park7), inflammation (Casp4), lipid metab. (Abca1), signal transduction (Gnb5) and neurogenesis (Plat). Our results tighten the link of vitamin D and AD and underline that vitamin D influences several genes also in brain, highlighting that a strong link not only to AD but also to other neurodegenerative diseases might exist.
- 207Uberti, F.; Morsanuto, V.; Bardelli, C.; Molinari, C. Protective Effects of 1α,25-Dihydroxyvitamin D3 on Cultured Neural Cells Exposed to Catalytic Iron. Physiol. Rep. 2016, 4 (11), e12769, DOI: 10.14814/phy2.12769
- 208Ibi, M.; Sawada, H.; Nakanishi, M.; Kume, T.; Katsuki, H.; Kaneko, S.; Shimohama, S.; Akaike, A. Protective Effects of 1α,25-(OH)2D3 against the Neurotoxicity of Glutamate and Reactive Oxygen Species in Mesencephalic Culture. Neuropharmacology 2001, 40 (6), 761– 771, DOI: 10.1016/S0028-3908(01)00009-0[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjtleqtL0%253D&md5=aa63e7fb5e85e532aff42c09a5e5656fProtective effects of 1α,25-(OH)2D3 against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic cultureIbi, M.; Sawada, H.; Nakanishi, M.; Kume, T.; Katsuki, H.; Kaneko, S.; Shimohama, S.; Akaike, A.Neuropharmacology (2001), 40 (6), 761-771CODEN: NEPHBW; ISSN:0028-3908. (Elsevier Science Ltd.)This study was undertaken to det. whether 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2D3], an active metabolite of vitamin D, protects dopaminergic neurons against the neurotoxic effects of glutamate and dopaminergic toxins using rat mesencephalic culture. Brief glutamate exposure elicited cytotoxicity in both dopaminergic and non-dopaminergic neurons. Pretreatment, but not co-administration, of 1α,25-(OH)2D3 protected both types of neurons against the cytotoxicity of glutamate in a concn.- and time-dependent manner. The neuroprotective effect of 1α,25-(OH)2D3 was inhibited by the protein synthesis inhibitor, cycloheximide. To investigate the mechanisms of these neuroprotective effects, the authors examd. the effects of 1α,25-(OH)2D3 on neurotoxicity induced by calcium ionophore and reactive oxygen species (ROS). Pretreatment with 1α,25-(OH)2D3 protected both types of neurons against the cytotoxicity induced by A23187 in a concn.-dependent manner. Furthermore, 24-h pretreatment with 1α,25-(OH)2D3 concn.-dependently protected both types of neurons from ROS-induced cytotoxicity. A 24-h incubation with 1α,25-(OH)2D3 inhibited the increase in intracellular ROS level following H2O2 exposure. A 24-h exposure to 1-methyl-4-phenylpyridium ion (MPP+) or 6-hydroxydopamine (6-OHDA) exerted selective neurotoxicity on dopaminergic neurons, and these neurotoxic effects were ameliorated by 1α,25-(OH)2D3. These results suggest that 1α,25-(OH)2D3 provides protection of dopaminergic neurons against cytotoxicity induced by glutamate and dopaminergic toxins by facilitating cellular functions that reduce oxidative stress.
- 209Zhang, D.; Li, M.; Dong, Y.; Zhang, X.; Liu, X.; Chen, Z.; Zhu, Y.; Wang, H.; Liu, X.; Zhu, J.; Shen, Y.; Korner, H.; Ying, S.; Fang, S.; Shen, Y. 1α,25-Dihydroxyvitamin D3 up-Regulates IL-34 Expression in SH-SY5Y Neural Cells. Innate Immun. 2017, 23 (7), 584– 591, DOI: 10.1177/1753425917725391[Crossref], [PubMed], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFGls7vM&md5=9313138b57a98984dca0e89483b6b76f1α,25-Dihydroxyvitamin D3 up-regulates IL-34 expression in SH-SY5Y neural cellsZhang, Dong; Li, Miaomiao; Dong, Yang; Zhang, Xinhui; Liu, Xingyun; Chen, Zhangming; Zhu, Yongji; Wang, Huiming; Liu, Xuwen; Zhu, Jialiang; Shen, Yujun; Korner, Heinrich; Ying, Songcheng; Fang, Shengyun; Shen, YuxianInnate Immunity (2017), 23 (7), 584-591CODEN: IINMCB; ISSN:1753-4259. (Sage Publications Ltd.)Vitamin D supplementation is regarded as a novel approach to treat Alzheimer's disease, but the underlying mechanism remains elusive. The cytokine IL-34 provides strong neuroprotective and survival signals in brain injury and neurodegeneration and could be an immunol. mediator for the vitamin D-induced protection. The aim of this study was to investigate whether human IL-34 is up-regulated in neuronal cells by the hormonally active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3]. We found that IL-34 was detectable in a variety of cell lines and its expression was strongly induced in SH-SY5Y neural cells in a dose- and time-dependent manner by 1α,25(OH)2D3 through the vitamin D receptor (VDR). Furthermore, we identified the core promoter of IL-34 gene and a VDR binding site (CGCCCT) that was required for 1α,25(OH)2D3-induced IL-34 expression. These findings suggest that the induction of IL-34 expression by 1α,25(OH)2D3 may constitute a mechanism that explains the protective function of vitamin D in Alzheimer's disease.
- 210Jiao, K.-P.; Li, S.-M.; Lv, W.-Y.; Jv, M.-L.; He, H.-Y. Vitamin D3 Repressed Astrocyte Activation Following Lipopolysaccharide Stimulation in Vitro and in Neonatal Rats. NeuroReport 2017, 28 (9), 492– 497, DOI: 10.1097/WNR.0000000000000782[Crossref], [PubMed], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnsFehsL8%253D&md5=519557ce6d76a0b6967f43acff03a170Vitamin D3 repressed astrocyte activation following lipopolysaccharide stimulation in vitro and in neonatal ratsJiao, Ke-Ping; Li, Shao-Min; Lv, Wen-Yan; Jv, Ming-Liang; He, Hai-YanNeuroReport (2017), 28 (9), 492-497CODEN: NERPEZ; ISSN:0959-4965. (Lippincott Williams & Wilkins)Vitamin D3 has been reported to be an immunity modulator and high levels of vitamin D3 are correlated with a decreased risk for developing diseases in the central nervous system. Astrocytes are important immune cells and contribute toward inflammation during neurol. diseases. The vitamin D receptor has been reported to be expressed in astrocytes; however, the effect of vitamin D3 on astrocyte activation has not been studied. Here, we found that lipopolysaccharide stimulation in astrocytes could enhance the expression of vitamin D receptor and Cyp27B1, which encodes the enzyme for converting vitamin D3 into its active form. Vitamin D3 suppressed the expression of proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, vascular endothelial growth factor, and also TLR4 in activated astrocytes. Astrocyte activation was further found to be suppressed after the administration of vitamin D3 in neonatal rats injected with lipopolysaccharide in vivo. We demonstrated the antiactivation effect of vitamin D3 in astrocytes after lipopolysaccharide stimulation. Considering the function of reactive astrocytes in augmenting inflammatory response in neurodegeneration and brain injury, the finding that vitamin D3 administration may inhibit astrocyte activation may be potentially useful for the treatment of central nervous system disorders.
- 211Dursun, E.; Gezen-Ak, D.; Yilmazer, S. A Novel Perspective for Alzheimer’s Disease: Vitamin D Receptor Suppression by Amyloid-β and Preventing the Amyloid-β Induced Alterations by Vitamin D in Cortical Neurons. Journal of Alzheimer’s Disease 2011, 23 (2), 207– 219, DOI: 10.3233/JAD-2010-101377[Crossref], [PubMed], [CAS], Google Scholar211https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1Wjsbs%253D&md5=4fb64de69281683840b3723ce895ccbdA Novel Perspective for Alzheimer's Disease: Vitamin D Receptor Suppression by Amyloid-β and Preventing the Amyloid-β Induced Alterations by Vitamin D in Cortical NeuronsDursun, Erdinc; Gezen-Ak, Duygu; Yilmazer, SelmaJournal of Alzheimer's Disease (2011), 23 (2), 207-219CODEN: JADIF9; ISSN:1387-2877. (IOS Press)Amyloid-β (Aβ) is the core component of amyloid plaques of Alzheimer's disease (AD). The effects of Aβ include damage to neuronal plasma membrane, disruption of Ca2+ homeostasis, and alterations of neurotrophic factor levels. The aim of this study was to det. the effects of Aβ treatment on vitamin D receptor (VDR), L-type voltage sensitive calcium channels A1C (LVSCC A1C), NGF, and observing the effects of vitamin D treatment on Aβ induced alterations in primary cortical neurons. As to the latter, we aimed to test the suggested neuroprotective role of vitamin D as a neglected neurosteroid. The expressions of VDR and LVSCC A1C were studied with qRT-PCR and Western blotting. NGF and cytotoxicity levels were detd. by ELISA. Apoptotic cell death was investigated with caspase-3 protein expression by Western blotting. Our results showed that the Aβ triggers neurodegeneration not only by inducing LVSCC A1C expression and NGF levels and but also by dramatically suppressing VDR expression. Administration of vitamin D to this model protected neurons by preventing cytotoxicity and apoptosis, and also by downregulating LVSCC A1C and upregulating VDR. Addnl., vitamin D brought NGF expression to a state of equil. and did not show its apoptosis inducing effects. Consequently, prevention of Aβ toxicity which was one of the major component of AD type pathol. by vitamin D treatment and understanding how Aβ effects vitamin D related pathways, might open up new frontiers in clarifying mol. mechanisms of neurodegeneration and provide basis for novel perspectives in both preventing and treating AD.
- 212Niino, M. Vitamin D and Its Immunoregulatory Role in Multiple Sclerosis. Drugs Today (Barc) 2010, 46 (4), 279– 290, DOI: 10.1358/dot.2010.46.4.1476498[Crossref], [PubMed], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3czmsVGitA%253D%253D&md5=129df007c7385d404b98e45d3b64e116Vitamin D and its immunoregulatory role in multiple sclerosisNiino MasaakiDrugs of today (Barcelona, Spain : 1998) (2010), 46 (4), 279-90 ISSN:1699-3993.Mapping the distribution of multiple sclerosis (MS) reveals a high prevalence of the disease in high-latitude areas, suggesting a positive relationship between vitamin D and MS. Vitamin D is known to play an important role in bone and mineral homeostasis. It has recently been reported that several types of immune cells express vitamin D receptors and that vitamin D has strong immune-modulating effects. Vitamin D and its analogues inhibited experimental autoimmune encephalomyelitis (EAE, an animal model of MS) and there have been reports of small clinical trials on the treatment of MS with vitamin D. Furthermore, there have been discussions on the association between vitamin D levels and MS and about the genetic risk of vitamin D receptor (VDR) gene polymorphisms in MS. The current review discusses the immunological functions of vitamin D, the association between vitamin D and MS and expectations regarding the role of vitamin D in future treatments of MS.
- 213Kim, H.; Shin, J.-Y.; Lee, Y.-S.; Yun, S. P.; Maeng, H.-J.; Lee, Y. Brain Endothelial P-Glycoprotein Level Is Reduced in Parkinson’s Disease via a Vitamin D Receptor-Dependent Pathway. Int. J. Mol. Sci. 2020, 21 (22), 8538, DOI: 10.3390/ijms21228538[Crossref], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFyhu7zI&md5=93f5ee512d5e3e0ccd9540c3d31df6eaBrain endothelial P-glycoprotein level is reduced in Parkinson's disease via a vitamin D receptor-dependent pathwayKim, Hyojung; Shin, Jeong-Yong; Lee, Yun-Song; Yun, Seung Pil; Maeng, Han-Joo; Lee, YunjongInternational Journal of Molecular Sciences (2020), 21 (22), 8538CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)The progressive neurodegeneration in Parkinson's disease (PD) is accompanied by neuroinflammation and endothelial vascular impairment. Although the vitamin D receptor (VDR) is expressed in both dopamine neurons and brain endothelial cells, its role in the regulation of endothelial biol. has not been explored in the context of PD. In a 6-hydroxydopamine (6-OHDA)-induced PD mouse model, we obsd. reduced transcription of the VDR and its downstream target genes, CYP24 and MDR1a. The 6-OHDA-induced transcriptional repression of these genes were recovered after the VDR ligand-1α25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment. Similarly, reduced vascular protein expression of P-glycoprotein (P-gp), encoded by MDR1a, after 6-OHDA administration was reversed by 1,25(OH)2D3. Moreover, marked redn. of endothelial P-gp expression with concomitant α-synuclein aggregation was found in a combinatorial AAV-α-Syn/α-Syn preformed fibril (PFF) injection mouse model and postmortem PD brains. Supporting the direct effect of α-synuclein aggregation on endothelial biol., PFF treatment of human umbilical vein endothelial cells (HUVECs) was sufficient to induce α-synuclein aggregation and repress transcription of the VDR. PFF-induced P-gp downregulation and impaired functional activity in HUVECs completely recovered after 1,25(OH)2D3 treatment. Taken together, our results suggest that a dysfunctional VDR-P-gp pathway could be a potential target for the maintenance of vascular homeostasis in PD pathol. conditions.
- 214Maestro, M. A.; Molnár, F.; Carlberg, C. Vitamin D and Its Synthetic Analogs. J. Med. Chem. 2019, 62 (15), 6854– 6875, DOI: 10.1021/acs.jmedchem.9b00208[ACS Full Text], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmtFGmtL8%253D&md5=fe8f12486f400eb3e273b2f505e5cd43Vitamin D and its synthetic analogsMaestro, Miguel A.; Molnar, Ferdinand; Carlberg, CarstenJournal of Medicinal Chemistry (2019), 62 (15), 6854-6875CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. For many individuals, in particular during winter, supplementation with the secosteroid vitamin D3 is essential for the prevention of bone disorders, muscle weakness, autoimmune diseases, and possibly also different types of cancer. Vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as potent agonist of the transcription factor vitamin D receptor (VDR). Thus, vitamin D directly affects chromatin structure and gene regulation at thousands of genomic loci, i.e., the epigenome and transcriptome of its target tissues. Modifications of 1,25(OH)2D3 at its side-chain, A-ring, triene system, or C-ring, alone and in combination, as well as nonsteroidal mimics provided numerous potent VDR agonists and some antagonists. The nearly 150 crystal structures of VDR's ligand-binding domain with various vitamin D compds. allow a detailed mol. understanding of their action. This review discusses the most important vitamin D analogs presented during the past 10 years and mol. insight derived from new structural information on the VDR protein.
- 215Bishop, J. E.; Collins, E. D.; Okamura, W. H.; Norman, A. W. Profile of Ligand Specificity of the Vitamin D Binding Protein for 1α,25-dihydroxyvitamin D3 and Its Analogs. J. Bone Miner. Res. 1994, 9 (8), 1277– 1288, DOI: 10.1002/jbmr.5650090818[Crossref], [PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXns12juw%253D%253D&md5=794df4d261834964fec27e1c0d9c5500Profile of ligand specificity of the vitamin D binding protein for 1α,25-dihydroxyvitamin D3 and its analogsBishop, June E.; Collins, Elaine D.; Okamura, William H.; Norman, Anthony W.Journal of Bone and Mineral Research (1994), 9 (8), 1277-88CODEN: JBMREJ; ISSN:0884-0431.The profile of structural preference for the ligand binding domain of the human vitamin D binding protein (DBP) was detd. by steroid competition assay of 71 analogs of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3]. The following categories of structural modification were evaluated [values represent fold change; R = redn., I = increase in binding to the DBP from the ref. 1α,25(OH)2D3]: (1) deletion in the A ring of the 1α-hydroxyl (20-1600I); (2) conversion of the triene system to the previtamin form (6-40R); (3) addn. of substituents to carbon 11 of the C ring (4-14R); (4) inversion of the C/D ring junction (8-20R); (5) unsatn. of the D ring (16-ene; 4-140R); (6) replacement of hydrogen with deuterium atoms (no effect); alteration of the side chain by (7) adding or deleting carbon atoms (5-12R); (8) addn. of fluorines (0.2-10R); (9) presence of unsatn. (22-ene, 0-5R; 23-ene, 3R-10I; 23-yne, 5-20R); (10) addn. of hydroxyls (2-100R); and (11) addn. of an arom. ring (0-20I). Thus, the DBP ligand binding domain could tolerate only modest changes to the structure of 1α,25(OH)2D3 without a redn. in binding of the analog. The increases in binding seen in the arom. side chain and with a triple bond at carbon-23 may be indicative of a preferred conformation of the flexible 1α,25(OH)2D3 side chain. In addn., a comparison was made of the DBP ligand binding domain with that of the human HL-60 cell 1α,25(OH)2D3 nuclear receptor. Both ligand binding domains could equivalently accommodate to the presence of (1) a side-chain cyclopropyl group, (2) 22-ene or 23-yne, (3) lengthening the side chain by two carbons, (4) presence of four to six fluorine atoms, (5) substitution of an oxygen for carbon 22, and (6) presence of a 22-[m-(dimethylhydroxymethyl)phenyl] arom. group in the side chain. The DPB could tolerate better than the HL-60 cell receptor the presence of a 22-(p-hydroxyphenyl) arom. group in the side chain and the absence of the 1α-hydroxyl. In contrast, the HL-60 cell receptor could tolerate better than the DBP the following structural modifications: presence of a 16-ene, or 16-ene plus 23-yne unsatn., and presence of an 11β-hydroxyl.
- 216Saito, N.; Matsunaga, T.; Saito, H.; Anzai, M.; Takenouchi, K.; Miura, D.; Namekawa, J.; Ishizuka, S.; Kittaka, A. Further Synthetic and Biological Studies on Vitamin D Hormone Antagonists Based on C24-Alkylation and C2α-Functionalization of 25-Dehydro-1α- Hydroxyvitamin D3–26,23-Lactones. J. Med. Chem. 2006, 49 (24), 7063– 7075, DOI: 10.1021/jm060797q[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFKlurbO&md5=f361104793a47a52e79eb358c23f78dbFurther Synthetic and Biological Studies on Vitamin D Hormone Antagonists Based on C24-Alkylation and C2α-Functionalization of 25-Dehydro-1α-hydroxyvitamin D3-26,23-lactonesSaito, Nozomi; Matsunaga, Toshihiro; Saito, Hiroshi; Anzai, Miyuki; Takenouchi, Kazuya; Miura, Daishiro; Namekawa, Jun-ichi; Ishizuka, Seiichi; Kittaka, AtsushiJournal of Medicinal Chemistry (2006), 49 (24), 7063-7075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)An efficient synthesis and the biol. evaluation of 80 novel analogs of 25-dehydro-1α-hydroxyvitamin D3-26,23S-lactone I (TEI-9647) and its 23R epimer in which the lactone ring was systematically functionalized by introduction of a C1 to C4 primary alkyl group at the C24 position (5 sets of 4 diastereomers), together with their C2α-Me, 3-hydroxypropyl, and 3-hydroxypropoxy-substituted derivs. were described. The triene structure of the vitamin D3 was constructed using palladium-catalyzed alkenylative cyclization of the A-ring precursor enyne with the CD-ring counterpart bromoolefin having the C24-alkylated lactone moiety on the side chain. The CD-ring precursors having 23,24-cis lactones were prepd. by using a chromium-mediated syn-selective allylation-lactonization process, and the 23,24-trans lactone derivs. were derived from these via inversion of the C23 stereochem. The biol. evaluation revealed that both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition of vitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length of the primary alkyl group on the lactone ring. Furthermore, the C2α-functionalization of the C24-alkylated vitamin D3 lactones dramatically enhanced their biol. activities. The most potent compd. to emerge, (23S,24S)-2α-(3-hydroxypropoxy)-24-Pr exhibited almost 1000-fold stronger antagonistic activity (IC50 = 7.4 pM) than I (IC50 = 6.3 nM).
- 217Wiberg, K.; Ljunghall, S.; Binderup, L.; Ljunggren, Ö. Studies on Two New Vitamin D Analogs, EB 1089 and KH 1060: Effects on Bone Resorption and Osteoclast Recruitment in Vitro. Bone 1995, 17 (4), 391– 395, DOI: 10.1016/S8756-3282(95)00246-4[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXpslWktrg%253D&md5=5b9302cde09afb7cb9d5611b917c084aStudies on two new vitamin D analogs, EB 1089 and KH 1060: effects on bone resorption and osteoclast recruitment in vitroWiberg, K.; Ljunghall, S.; Binderup, L.; Ljunggren, Oe.Bone (New York) (1995), 17 (4), 391-5CODEN: BONEDL; ISSN:8756-3282. (Elsevier)The effects on bone resorption of 2 new potent antiproliferative vitamin D3 analogs, EB 1089 and KH 1060, were investigated by studying recruitment of osteoclasts in murine bone marrow cultures and 45Ca release from prelabeled neonatal mouse calvarial bones. Binding studies to vitamin D receptor protein from human osteosarcoma MG-63 cells demonstrated kd values of 8.5 × 10-11 for calcitriol (1α,25(OH)2D3), 6.5 × 10-11 for KH 1060, and 2.7 × 10-10 for EB 1089. 1α,25(OH)2D3 and EB 1089 were equipotent stimulators of osteoclast recruitment in murine bone marrow cultures, with EC50 values of 10-10M, whereas KH 1060 was about 10-fold more potent, with an EC50 of 10-11M. In serum-free media, 1α,25(OH)2D3 enhanced 45Ca release from neonatal mouse calvarial bones with an EC50 of 10-11M, but in the presence of 10% fetal calf serum (FCS) the stimulatory effect was diminished, with a threshold value of 10-10M. EB 1089 stimulated bone resorption with an estd. EC50 of 3 × 10-11M, whereas KH 1060 was about 10-fold more potent than 1α,25(OH)2D3, and it stimulated bone resorption with an EC50 of 10-12M. The effects of EB 1089 and KH 1060 on 45Ca release were not affected by the addn. of 10% FCS. Addn. of vitamin D-binding protein to serum-free incubations of neonatal mouse calvarial bones inhibited the bone-resorbing effect of 1α,25(OH)2D3 but did not affect EB 1089- and KH 1060-induced 45Ca release. These data show that the kd values for the binding to vitamin D receptors are similar to the EC50 values for stimulation of bone resorption and osteoclast differentiation, in vitro, for 1α,25(OH)2D3, EB 1089, and KH 1060. The discrepancy in the effect of FCS on 45Ca release induced by 1α,25(OH)2D3 and the new analogs suggests that EB 1089 and KH 1060 do not bind to vitamin D-binding protein, indicating that pharmacokinetic differences may partially explain their lesser calcemic effects in vivo.
- 218Germain, P.; Chambon, P.; Eichele, G.; Evans, R. M.; Lazar, M. A.; Leid, M.; De Lera, A. R.; Lotan, R.; Mangelsdorf, D. J.; Gronemeyer, H. International Union of Pharmacology. LXIII. Retinoid X Receptors. Pharmacol. Rev. 2006, 58 (4), 760– 772, DOI: 10.1124/pr.58.4.7[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28npsFOhtw%253D%253D&md5=9d9ed3201419f63fab5ca74043cc0a19International Union of Pharmacology. LXIII. Retinoid X receptorsGermain Pierre; Chambon Pierre; Eichele Gregor; Evans Ronald M; Lazar Mitchell A; Leid Mark; De Lera Angel R; Lotan Reuben; Mangelsdorf David J; Gronemeyer HinrichPharmacological reviews (2006), 58 (4), 760-72 ISSN:0031-6997.The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. RARs bind both all-trans- and 9-cis-RA, whereas only the 9-cis-RA stereoisomer binds to RXRs. As RXR/RAR heterodimers, these receptors control the transcription of RA target genes through binding to RA-response elements. This review is focused on the structure, mode of action, ligands, expression, and pharmacology of RXRs. Given their role as common partners to many other members of the nuclear receptor superfamily, these receptors have been the subject of intense scrutiny. Moreover, and despite numerous studies since their initial discovery, RXRs remain enigmatic nuclear receptors, and there is still no consensus regarding their role. Indeed, multiple questions about the actual biological role of RXRs and the existence of an endogenous ligand have still to be answered.
- 219de Lera, A. R.; Bourguet, W.; Altucci, L.; Gronemeyer, H. Design of Selective Nuclear Receptor Modulators: RAR and RXR as a Case Study. Nat. Rev. Drug Discovery 2007, 6 (10), 811– 820, DOI: 10.1038/nrd2398[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFSgsLzN&md5=223ff5473631d321c2e81bb76b986253Design of selective nuclear receptor modulators: RAR and RXR as a case studyde Lera, Angel R.; Bourguet, William; Altucci, Lucia; Gronemeyer, HinrichNature Reviews Drug Discovery (2007), 6 (10), 811-820CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Retinoic acid receptors (RARs) are important drug targets for cancer therapy and prevention, and the potential of rexinoids for the treatment of metabolic diseases is increasingly being recognized. This article reviews recent structural data for RARs and retinoid X receptors (RXRs), discusses strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general. Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are members of the nuclear receptor superfamily whose effects on cell growth and survival can be modulated therapeutically by small-mol. ligands. Although compds. that target these receptors are powerful anticancer drugs, their use is limited by toxicity. An improved understanding of the structural biol. of RXRs and RARs and recent advances in the chem. synthesis of modified retinoid and rexinoid ligands should enable the rational design of more selective agents that might overcome such problems. Here, the authors review structural data for RXRs and RARs, discuss strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general.
- 220Dominguez, M.; Alvarez, S.; de Lera, A. R. Natural and Structure-Based RXR Ligand Scaffolds and Their Functions. Curr. Top. Med. Chem. 2017, 17 (6), 631– 662, DOI: 10.2174/1568026616666160617072521[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1ektbk%253D&md5=1e41e2fd5d7ed6ae48caa38cddbe306dNatural and Structure-based RXR Ligand Scaffolds and Their FunctionsDominguez, Marta; Alvarez, Susana; de Lera, Angel R.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2017), 17 (6), 631-662CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)Retinoid X receptors (RXRs) are promiscuous partners of heterodimeric assocns. with other members of the Nuclear Receptor (NR) superfamily. Through these liaisons RXR ligands ("rexinoids") either transcriptionally activate on their own the "permissive" subclass of heterodimers (PPAR/RXR, LXR/RXR, FXR/RXR) or synergize with partner ligands in the "non-permissive" subclass of heterodimers (RAR/RXR, VDR/RXR and TR/RXR). The nature and extent of the interaction of the ligand-receptor complexes with co-regulators, which is cell and context-dependent, results ultimately in transcriptional modulation of cognate gene networks. RXR modulators hold therapeutical potential for the treatment of cancer and other diseases related to nutrient acquisition and disposal, among them metabolic diseases. A rexinoid (bexarotene) has indeed reached the clinic for the treatment of cutaneous T-cell lymphoma. The modulation of RXR function by rexinoids acting as agonists, partial agonists, inverse agonists or antagonists is encoded in the structure of the ligand-receptor complexes. A very large no. of rexinoids with a wide structural diversity has been published. In addn. to natural products and other ligands discovered by HTS or mere serendipity, most rexinoids have been rationally designed based on the structures of existing complexes with RXR detd. by X-Ray or based on Mol. Modeling. Although the structural rationale for the modulation of the ligand-receptor complexes is reasonably well understood, it has not yet been possible to predict the correlation between ligand structure and physiol. response, particularly in the case of heterodimer-selective rexinoids.
- 221Chaikuad, A.; Pollinger, J.; Rühl, M.; Ni, X.; Kilu, W.; Heering, J.; Merk, D. Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms. Int. J. Mol. Sci. 2020, 21 (22), 8457, DOI: 10.3390/ijms21228457[Crossref], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFyhtLjL&md5=9f8ebbf6fe24cd7a000346b87de48e9bComprehensive set of tertiary complex structures and palmitic acid binding provide molecular insights into ligand design for RXR isoformsChaikuad, Apirat; Pollinger, Julius; Ruehl, Michael; Ni, Xiaomin; Kilu, Whitney; Heering, Jan; Merk, DanielInternational Journal of Molecular Sciences (2020), 21 (22), 8457CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically obsd. for RXR agonists, likely due to the lack of isoform selectivity, limit chemotherapeutic application of currently available RXR ligands. The three human RXR isoforms exhibit different expression patterns; however, they share high sequence similarity, presenting a major obstacle toward the development of subtype-selective ligands. Here, we report the discovery of the satd. fatty acid, palmitic acid, as an RXR ligand and disclose a uniform set of crystal structures of all three RXR isoforms in an active conformation induced by palmitic acid. A structural comparison revealed subtle differences among the RXR subtypes. We also obsd. an ability of palmitic acid as well as myristic acid and stearic acid to induce recruitment of steroid receptor co-activator 1 to the RXR ligand-binding domain with low micromolar potencies. With the high, millimolar endogenous concns. of these highly abundant lipids, our results suggest their potential involvement in RXR signaling.
- 222Schierle, S.; Merk, D. Therapeutic Modulation of Retinoid X Receptors - SAR and Therapeutic Potential of RXR Ligands and Recent Patents. Expert Opin. Ther. Pat. 2019, 29 (8), 605– 621, DOI: 10.1080/13543776.2019.1643322[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVWjsbbK&md5=963ecfd85c230fdfa5846a41beb5dd3cTherapeutic modulation of retinoid X receptors - SAR and therapeutic potential of RXR ligands and recent patentsSchierle, Simone; Merk, DanielExpert Opinion on Therapeutic Patents (2019), 29 (8), 605-621CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)A review. Retinoid X receptor (RXR) agonists have a limited role in cancer therapy with bexarotene and alitretinoin as approved drugs but their use is limited by adverse effects. Several evidence from in vitro, in vivo, and small clin. studies points to various further potential applications of RXR ligands in neurodegenerative and inflammatory diseases. The authors review known RXR ligand classes with their key structure-activity relationships and recent reports on pharmacol. effects of RXR modulation. Based on these aspects, the authors evaluate recent patents claiming novel RXR ligands or their use. While the use of RXR modulators has been claimed in several novel and promising indications, little progress has been made in the development of innovative rexinoids with improved (subtype-)selectivity. Next-generation RXR modulators that selectively target the RXR subtypes for individual indications may be required to exhaustively exploit the therapeutic potential of RXRs.
- 223Egea, P. F.; Mitschler, A.; Moras, D. Molecular Recognition of Agonist Ligands by RXRs. Mol. Endocrinol. 2002, 16 (5), 987– 997, DOI: 10.1210/mend.16.5.0823[Crossref], [PubMed], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjsFGhsL8%253D&md5=c1fa963b975b03e1191d193df8962627Molecular recognition of agonist ligands by RXRsEgea, Pascal F.; Mitschler, Andre; Moras, DinoMolecular Endocrinology (2002), 16 (5), 987-997CODEN: MOENEN; ISSN:0888-8809. (Endocrine Society)The nuclear receptor RXR is an obligate partner in many signal transduction pathways. We report the high-resoln. structures of two complexes of the human RXRα ligand-binding domain specifically bound to two different and chem. unrelated agonist compds.: docosahexaenoic acid, a natural deriv. of eicosanoic acid, present in mammalian cells and recently identified as a potential endogenous RXR ligand in the mouse brain, and the synthetic ligand BMS 649. In both structures the RXR-ligand-binding domain forms homodimers and exhibits the active conformation previously obsd. with 9-cis-RA. Anal. of the differences in ligand-protein contacts (predominantly van der Waals forces) and binding cavity geometries and vols. for the several agonist-bound RXR structures clarifies the structural features important for ligand recognition. The L-shaped ligand-binding pocket adapts to the diverse ligands, esp. at the level of residue N306, which might thus constitute a new target for drug-design. Despite its highest affinity 9-cis-RA displays the lowest no. of ligand-protein contacts. These structural results support the idea that docosahexaenoic acid and related fatty acids could be natural agonists of RXRs and question the real nature of the endogenous ligand(s) in mammalian cells.
- 224Zetterstrom, R. H.; Lindqvist, E.; De Urquiza, A. M.; Tomac, A.; Eriksson, U.; Perlmann, T.; Olson, L. Role of Retinoids in the CNS : Differential Expression of Retinoid Binding Proteins and Receptors and Evidence for Presence of Retinoic Acid. Eur. J. Neurosci. 1999, 11 (2), 407– 416, DOI: 10.1046/j.1460-9568.1999.00444.x[Crossref], [PubMed], [CAS], Google Scholar224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1M7ntF2gsg%253D%253D&md5=cd0fdeef9529344c16ec83832bc07216Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acidZetterstrom R H; Lindqvist E; Mata de Urquiza A; Tomac A; Eriksson U; Perlmann T; Olson LThe European journal of neuroscience (1999), 11 (2), 407-16 ISSN:0953-816X.Retinoic acid (RA), a retinoid metabolite, acts as a gene regulator via ligand-activated transcription factors, known as retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both existing in three different subtypes, alpha, beta and gamma. In the intracellular regulation of retinoids, four binding proteins have been implicated: cellular retinol binding protein (CRBP) types I and II and cellular retinoic acid binding protein (CRABP) types I and II. We have used in situ hybridization to localize mRNA species encoding CRBP- and CRABP I and II as well as all the different nuclear receptors in the developing and adult rat and mouse central nervous system (CNS), an assay to investigate the possible presence of RA, and immunohistochemistry to also analyse CRBP I- and CRABP immunoreactivity (IR). RXRbeta is found in most areas while RARalpha and -beta and RXRalpha and -gamma show much more restricted patterns of expression. RARalpha is found in cortex and hippocampus and RARbeta and RXRgamma are both highly expressed in the dopamine-innervated areas caudate/putamen, nucleus accumbens and olfactory tubercle. RARgamma could not be detected in any part of the CNS. Using an in vitro reporter assay, we found high levels of RA in the developing striatum. The caudate/putamen of the developing brain showed strong CRBP I-IR in a compartmentalized manner, while at the same time containing many evenly distributed CRABP I-IR neurons. The CRBP I- and CRABP I-IR patterns were closely paralleled by the presence of the corresponding transcripts. The specific expression pattern of retinoid-binding proteins and nuclear retinoid receptors as well as the presence of RA in striatum suggests that retinoids are important in many brain structures and emphasizes a role for retinoids in gene regulatory events in postnatal and adult striatum.
- 225Ferré, S.; Fredholm, B. B.; Morelli, M.; Popoli, P.; Fuxe, K. Adenosine – Dopamine Receptor – Receptor Interactions as an Integrative Mechanism in the Basal Ganglia. Trends Neurosci. 1997, 20 (10), 482– 487, DOI: 10.1016/S0166-2236(97)01096-5[Crossref], [PubMed], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmsFKisr4%253D&md5=986e1e4f2207c6844f000db83557cca8Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal gangliaFerre, Sergi; Fredholm, Bertil B.; Morelli, Micaela; Popoli, Patrizia; Fuxe, KjellTrends in Neurosciences (1997), 20 (10), 482-487CODEN: TNSCDR; ISSN:0166-2236. (Elsevier)A review, with 48 refs. Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the motor depressant effects of adenosine receptor agonists and the motor stimulant effects of adenosine receptor antagonists, such as caffeine. The GABAergic striatopallidal neurons are regulated by interacting adenosine A2A and dopamine D2 receptors. The GABAergic striatonigral and striatoentopeduncular neurons seem to be regulated by interacting adenosine A1 and dopamine D1 receptors. Furthermore, behavioral studies have revealed interactions between adenosine A2A and dopamine D1 receptors that occur at the network level. These adenosine-dopamine receptor-receptor interactions might offer new therapeutic leads for basal ganglia disorders.
- 226Moreno, S.; Farioli-Vecchioli, S.; Cerù, M. P. Immunolocalization of Peroxisome Proliferator-Activated Receptors and Retinoid X Receptors in the Adult Rat CNS. Neuroscience 2004, 123 (1), 131– 145, DOI: 10.1016/j.neuroscience.2003.08.064[Crossref], [PubMed], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXps1Ontb0%253D&md5=436ec9624d1520e4270028d128342b92Immunolocalization of peroxisome proliferator-activated receptors and retinoid x receptors in the adult rat CNSMoreno, S.; Farioli-Vecchioli, S.; Ceru, M. P.Neuroscience (Oxford, United Kingdom) (2004), 123 (1), 131-145CODEN: NRSCDN; ISSN:0306-4522. (Elsevier Science Ltd.)Peroxisome proliferator-activated and retinoid X receptors (PPARs and RXRs) are transcription factors belonging to the steroid hormone receptor superfamily. Upon activation by their ligands, PPARs and RXRs bind to their target genes as heterodimers. Ligands of these receptors include lipophilic mols., such as retinoids, fatty acids and eicosanoids, the importance of which in the metab. and functioning of the nervous tissue is well documented. The immunohistochem. distribution of PPARs and RXRs in the CNS of the adult rat was studied by means of a sensitive biotinyl-tyramide method. All PPAR (α, β/δ and γ) and RXR (α, β and γ) isotypes were detected and found to exhibit specific patterns of localization in the different areas of the brain and spinal cord. The presence of the nuclear receptors was obsd. in both neuronal and glial cells. While PPAR β/δ and RXR β showed a widespread distribution, α and γ isotypes exhibited a more restricted pattern of expression. The frontal cortex, basal ganglia, reticular formation, some cranial nerve nuclei, deep cerebellar nuclei, and cerebellar Golgi cells appeared rather rich in all studied receptors. Based on our data, we suggest that in the adult CNS, PPARs and RXRs, besides playing roles common to many other tissues, may have specific functions in regulating the expression of genes involved in neurotransmission, and therefore play roles in complex processes, such as aging, neurodegeneration, learning and memory.
- 227Huang, J. K.; Jarjour, A. A.; Nait Oumesmar, B.; Kerninon, C.; Williams, A.; Krezel, W.; Kagechika, H.; Bauer, J.; Zhao, C.; Baron-Van Evercooren, A.; Chambon, P.; Ffrench-Constant, C.; Franklin, R. J. M. Retinoid X Receptor Gamma Signaling Accelerates CNS Remyelination. Nat. Neurosci. 2011, 14 (1), 45– 53, DOI: 10.1038/nn.2702[Crossref], [PubMed], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFajurjL&md5=376bc307b9d9726eb612b6bc8366e733Retinoid X receptor gamma signaling accelerates CNS remyelinationHuang, Jeffrey K.; Jarjour, Andrew A.; Oumesmar, Brahim Nait; Kerninon, Christophe; Williams, Anna; Krezel, Wojciech; Kagechika, Hiroyuki; Bauer, Julien; Zhao, Chao; Baron-Van Evercooren, Anne; Chambon, Pierre; ffrench-Constant, Charles; Franklin, Robin J. M.Nature Neuroscience (2011), 14 (1), 45-53CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)The mol. basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the sep. stages of spontaneous remyelination that follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-γ is a pos. regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacol. target for regenerative therapy in the CNS.
- 228Hanafy, K. A.; Sloane, J. A. Regulation of Remyelination in Multiple Sclerosis. FEBS Lett. 2011, 585 (23), 3821– 3828, DOI: 10.1016/j.febslet.2011.03.048[Crossref], [PubMed], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFSis73P&md5=1fb2590498171cf217c8f19652602321Regulation of remyelination in multiple sclerosisHanafy, Khalid A.; Sloane, Jacob A.FEBS Letters (2011), 585 (23), 3821-3828CODEN: FEBLAL; ISSN:0014-5793. (Elsevier B.V.)A review. Multiple sclerosis is a common demyelinating disease that worsens over the course of disease, a significant problem in clin. management. Disability in MS is significantly promoted by poor repair and remyelination of lesions. Both oligodendrocyte recruitment and maturation defects are seen as major causes of poor remyelination in MS. The mechanisms behind impaired remyelination in animal models include involvement of the Notch1, wnt, and hyaluronan/TLR2 pathways. RXR/PPAR signaling has also more recently been identified as an important regulator of remyelination. The local inflammatory milieu also appears to play crit. and conflicting roles in promotion and inhibition of remyelination in MS. Understanding the forces regulating remyelination in MS represents an exciting and important initial step towards developing therapeutics targeting chronic disability in MS.
- 229Vaz, B.; de Lera, Á. R. Advances in Drug Design with RXR Modulators. Expert Opin. Drug Discovery 2012, 7 (11), 1003– 1016, DOI: 10.1517/17460441.2012.722992[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFOntbzJ&md5=8937d9930d5574a56c13415a954ae1c5Advances in drug design with RXR modulatorsVaz, Belen; de Lera, Angel R.Expert Opinion on Drug Discovery (2012), 7 (11), 1003-1016CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)A review. Introduction: Retinoid X receptors (subtypes RXRα or NR2B1, RXRβ or NR2B2 and RXRγ or NR2B3, which originate from three distinct genes) are promiscuous partners with heterodimeric assocns. to other members of the Nuclear Receptor (NR) superfamily. Some of the heterodimers are "permissive" and transcriptionally active in the presence of either an RXR ligand ("rexinoid") or a NR partner ligand, whereas others are "non-permissive" and unresponsive to rexinoids alone. In rodent models, rexinoids and partner agonists (mainly PPARγ, LXR, FXR) produce beneficial effects on insulin sensitization, diabetes and obesity, but secondary effects have also been noted, such as a raise in tryglyceride levels, suppression of the thyroid hormone axis and induction of hepatomegaly.Areas covered: The authors review recent advances in rexinoid design, including further optimization of known scaffolds, and the discovery of novel RXR modulators by virtual ligand screening or from bioactive natural products. The understanding of rexinoid functions in permissive and non-permissive heterodimers is firmly based on structural knowledge. By strenghtening or disrupting the interaction surface with coregulators rexinoids exert agonist or (partial) antagonist activities. The activity state of the heterodimer can also be fine-tuned by the cellular context and the nature of coregulators.Expert opinion: The synthetic chem. toolbox has provided a panel of agonists, partial (ant)agonists and/or heterodimer-selective rexinoids starting from existing, naturally occurring or serendipitously discovered scaffolds. These compds. have an unexplored therapeutic potential that might overcome some of the current limitations of rexinoids in therapy, such as hypertriglyceridemia.
- 230Koster, K. P.; Smith, C.; Valencia-Olvera, A. C.; Thatcher, G. R. J.; Tai, L. M.; LaDu, M. J. Rexinoids as Therapeutics for Alzheimer’s Disease: Role of APOE. Curr. Top. Med. Chem. 2017, 17 (6), 708– 720, DOI: 10.2174/1568026616666160617090227[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1ektLo%253D&md5=99e3cc09db5b6e42084ea846eb9d9963Rexinoids as Therapeutics for Alzheimer's Disease: Role of APOEKoster, Kevin P.; Smith, Conor; Valencia-Olvera, Ana C.; Thatcher, Gregory R. J.; Tai, Leon M.; LaDu, Mary JoCurrent Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2017), 17 (6), 708-720CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques, composed of amyloid-beta peptide (Aβ) and neurofibrillary tangles, composed of aberrantly phosphorylated tau. APOE4 is the greatest genetic risk factor for AD, increasing risk up to 12- fold with a double allele compared to APOE3. In contrast, APOE2 reduces AD risk ∼2-fold per allele. Accumulating evidence demonstrates that apolipoprotein E4 (apoE4) plays a multifactorial role in AD pathogenesis, although the exact mechanisms remain unclear. Further data support roles for apoE4 as a toxic gain of function or loss of pos. function in AD, a discrepancy that has significant implications for the future of apoE-directed therapeutics. However, recent evidence repurposing retinoid X receptor (RXR) agonists, or rexinoids, for the treatment of AD demonstrates conflicting, though potentially beneficial effects in familial AD-transgenic (FAD-Tg) mouse models. Of particular note is bexarotene (Targretin), a selective rexinoid previously utilized in cancer treatment emerging as a viable candidate for AD clin. trials. However, the mechanism of action of bexarotene and similar rexinoids remains controversial, particularly in the context of human APOE. In addn., rexinoids demonstrate distinct adverse event profiles in humans that may have greater detrimental effects in an elderly AD population. Therefore, this special issue review discusses the implications for rexinoiddirected therapeutic strategies in AD, the potential mechanistic targets, and future directions for the improvement of rexinoid-based therapies in AD.
- 231Corder, E. H.; Saunders, A. M.; Strittmatter, W. J.; Schmechel, D. E.; Gaskell, P. C.; Small, G. W.; Roses, A. D.; Haines, J. L.; Pericak-Vance, M. A. Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer’s Disease in Late Onset Families. Science 1993, 261 (5123), 921– 923, DOI: 10.1126/science.8346443[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmtVWjur8%253D&md5=69f2add123ded907ea61945b1de5b45fGene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset familiesCorder, E. H.; Saunders, A. M.; Strittmatter, W. J.; Schmechel, D. E.; Gaskell, P. C.; Small, G. W.; Roses, A. D.; Haines, J. L.; Pericak-Vance, M. A.Science (Washington, DC, United States) (1993), 261 (5123), 921-3CODEN: SCIEAS; ISSN:0036-8075.The apolipoprotein E type 4 allele (APOE-ε4) is genetically assocd. with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 yr with increasing no. of APOE-ε4 alleles in 42 families with late onset AD. Thus APOE-ε4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-ε4 was virtually sufficient to cause AD by age 80.
- 232Cosentino, S.; Scarmeas, N.; Helzner, E.; Glymour, M. M.; Brandt, J.; Albert, M.; Blacker, D.; Stern, Y. APOE Epsilon 4 Allele Predicts Faster Cognitive Decline in Mild Alzheimer Disease. Neurology 2008, 70 (19), 1842– 1849, DOI: 10.1212/01.wnl.0000304038.37421.cc[Crossref], [PubMed], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c3psFCntw%253D%253D&md5=2e53832aaf6d7afeb5457bcd9171329bAPOE epsilon 4 allele predicts faster cognitive decline in mild Alzheimer diseaseCosentino S; Scarmeas N; Helzner E; Glymour M M; Brandt J; Albert M; Blacker D; Stern YNeurology (2008), 70 (19 Pt 2), 1842-9 ISSN:.OBJECTIVE: To determine whether APOE epsilon 4 predicts rate of cognitive change in incident and prevalent Alzheimer disease (AD). METHODS: Individuals were recruited from two longitudinal cohort studies-the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based)--and were followed for an average of 4 years. Three samples of participants diagnosed with AD, with diverse demographic characteristics and baseline cognitive functioning, were studied: 1) 199 (48%) of the incident WHICAP cases; 2) 215 (54%) of the prevalent WHICAP cases; and 3) 156 (71%) of the individuals diagnosed with AD in the Predictors Study. Generalized estimating equations were used to test whether rate of cognitive change, measured using a composite cognitive score in WHICAP and the Mini-Mental State Examination in Predictors, varied as a function of epsilon 4 status in each sample. RESULTS: The presence of at least one epsilon 4 allele was associated with faster cognitive decline in the incident population-based AD group (p = 0.01). Parallel results were produced for the two prevalent dementia samples only when adjusting for disease severity or excluding the most impaired participants from the analyses. CONCLUSION: APOE epsilon 4 may influence rate of cognitive decline most significantly in the earliest stages of Alzheimer disease.
- 233Khachaturian, A. S.; Corcoran, C. D.; Mayer, L. S.; Zandi, P. P.; Breitner, J. C. S. Apolipoprotein E Epsilon4 Count Affects Age at Onset of Alzheimer Disease, but Not Lifetime Susceptibility: The Cache County Study. Arch. Gen. Psychiatry 2004, 61 (5), 518– 524, DOI: 10.1001/archpsyc.61.5.518[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXkslektbk%253D&md5=477d98c0284ec737d6b66fa4f02cf6b1Apolipoprotein E ε4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The cache county studyKhachaturian, Ara S.; Corcoran, Christopher D.; Mayer, Lawrence S.; Zandi, Peter P.; Breitner, John C. S.Archives of General Psychiatry (2004), 61 (5), 518-524CODEN: ARGPAQ; ISSN:0003-990X. (American Medical Association)The incidence of Alzheimer disease (AD) increases strongly with age, but little is known about the cumulative incidence of AD over a lifetime of 100 yr, or its relationship to the polymorphic APOE locus that encodes apolipoprotein E. APOE is a strong genetic risk factor for AD. The aim was to est. the occurrence of AD as a function of age and no. of APOE ε4 alleles; and to explore evidence for heterogeneity of AD risk related to APOE genotype and to other sources. Nonparametric and parametric survival analyses of AD incidence in prospective longitudinal study. Setting and Participants: A total of 3308 elderly residents of Cache County, Utah. Main Outcome Measures: Cumulative incidence of AD; in mixt. models assuming susceptible and non-susceptible individuals, the proportion of individuals not susceptible to AD at any age. Results: Models that assumed a proportion of invulnerable individuals provided strongly improved fit to the data. These models estd. the 100-yr lifetime incidence of AD at 72%, implying that 28% of individuals would not develop AD over any reasonable life expectancy. We confirmed the acceleration of AD onset in individuals with 1 or, esp., 2 APOE ε4 alleles, but obsd. no meaningful difference in 100-yr lifetime incidence related to no. of ε4 alleles. Conclusions: The APOE ε4 allele acts as a potent risk factor for AD by accelerating onset. However, the risk of AD appears heterogeneous in ways independent of APOE. Some individuals seem destined to escape AD, even over an extended lifespan. Their relative invulnerability may reflect other genes or environmental factors that can be investigated.
- 234Mandrekar-Colucci, S.; Landreth, G. E. Nuclear Receptors as Therapeutic Targets for Alzheimer’s Disease. Expert Opin. Ther. Targets 2011, 15 (9), 1085– 1097, DOI: 10.1517/14728222.2011.594043[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVWnt7zO&md5=b99a95828b8081ef50deea7fda13419bNuclear receptors as therapeutic targets for Alzheimer's diseaseMandrekar-Colucci, Shweta; Landreth, Gary E.Expert Opinion on Therapeutic Targets (2011), 15 (9), 1085-1097CODEN: EOTTAO; ISSN:1472-8222. (Informa Healthcare)A review. Introduction: Alzheimer's disease (AD) is characterized by the accumulation and extensive deposition of amyloid β (Aβ) in the parenchyma of the brain. This accumulation of amyloid is assocd. with perturbations in synaptic function, impairments in energy metab. and induction of a chronic inflammatory response which acts to promote neuronal loss and cognitive impairment. Areas covered: Currently, there are no drugs that target the underlying mechanisms of AD. Here, we propose a class of nuclear receptors as novel and promising new therapeutic targets for AD. This review summarizes the literature on nuclear receptors and their effects on AD-related pathophysiol. Expert opinion: Nuclear receptors are attractive targets for the treatment of AD due to their ability to facilitate degrdn. of Aβ, affect microglial activation and suppress the inflammatory milieu of the brain. Liver X receptor agonists have proven difficult to move into clin. trials as long-term treatment results in hepatic steatosis. It is our view that PPAR-γ activation remains a promising avenue for the treatment for AD; however, the poor BBB permeability of the currently available agonists and the neg. outcome of the Phase III clin. trials are likely to diminish interest in pursuing this target.
- 235Koldamova, R.; Fitz, N. F.; Lefterov, I. ATP-Binding Cassette Transporter A1: From Metabolism to Neurodegeneration. Neurobiol. Dis. 2014, 72A, 13– 21, DOI: 10.1016/j.nbd.2014.05.007
- 236Oram, J. F.; Vaughan, A. M. ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease. Circ. Res. 2006, 99 (10), 1031– 1043, DOI: 10.1161/01.RES.0000250171.54048.5c[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFKgurrK&md5=cd3ea59aeaea73d433b8ccaf958ad881ATP-Binding Cassette Cholesterol Transporters and Cardiovascular DiseaseOram, John F.; Vaughan, Ashley M.Circulation Research (2006), 99 (10), 1031-1043CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)A review. A hallmark of atherosclerotic cardiovascular disease (CVD) is the accumulation of cholesterol in arterial macrophages. Factors that modulate circulating and tissue cholesterol levels have major impacts on initiation, progression, and regression of CVD. Four members of the ATP-binding cassette (ABC) transporter family play important roles in this modulation. ABCA1 and ABCG1 export excess cellular cholesterol into the HDL pathway and reduce cholesterol accumulation in macrophages. ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. All 4 transporters are induced by the same sterol-sensing nuclear receptor system. ABCA1 expression and activity are also highly regulated posttranscriptionally by diverse processes. ABCA1 mutations can cause a severe HDL-deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. ABCG5 or ABCG8 mutations can cause sitosterolemia, in which patients accumulate cholesterol and plant sterols in the circulation and develop premature CVD. Disrupting Abca1 or Abcg1 in mice promotes accumulation of excess cholesterol in macrophages, and manipulating mouse macrophage ABCA1 expression affects atherogenesis. Overexpressing ABCG5 and ABCG8 in mice attenuates diet-induced atherosclerosis in assocn. with reduced circulating and liver cholesterol. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and inhibit transcription of all 4 transporters. Thus, impaired ABC cholesterol transporters might contribute to the enhanced atherogenesis assocd. with common inflammatory and metabolic disorders. Their beneficial effects on cholesterol homeostasis have made these transporters important new therapeutic targets for preventing and reversing CVD.
- 237Tai, L. M.; Mehra, S.; Shete, V.; Estus, S.; Rebeck, G. W.; Bu, G.; Ladu, M. J. Soluble ApoE/Aβ Complex: Mechanism and Therapeutic Target for APOE4-Induced AD Risk. Mol. Neurodegener. 2014, 9, 2, DOI: 10.1186/1750-1326-9-2[Crossref], [PubMed], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivVWktbw%253D&md5=287cdde0f7c3b6c8a35e579c7b19c215Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD riskTai, Leon M.; Mehra, Shipra; Shete, Varsha; Estus, Steve; Rebeck, G. William; Bu, Guojun; La Du, Mary JoMolecular Neurodegeneration (2014), 9 (), 2/1-2/14, 14 pp.CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)A review. The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer's disease (AD) compared to APOE2 and APOE3. Amyloid-β (Aβ), particularly in a sol. oligomeric form (oAβ), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of sol. oAβ are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oAβ levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with Aβ, namely apoE/Aβ complex, modulate Aβ levels. Specifically, we propose that compared to apoE3, apoE4-contg. lipoproteins are less lipidated, leading to less stable apoE4/Aβ complexes, resulting in reduced apoE4/Aβ levels and increased accumulation, particularly of oAβ. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed.
- 238Yu, C.; Youmans, K. L.; Ladu, M. J. Proposed Mechanism for Lipoprotein Remodelling in the Brain. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2010, 1801 (8), 819– 823, DOI: 10.1016/j.bbalip.2010.05.001[Crossref], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntlagsrk%253D&md5=28ccd42cd28cb04cb5415ad8abb8d49aProposed mechanism for lipoprotein remodelling in the brainYu, Chunjiang; Youmans, Katherine L.; La Du, Mary J.Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2010), 1801 (8), 819-823CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)A review. Lipoprotein remodelling in the periphery has been extensively studied. For example, the processing of nascent apoAI particles to cholesterol-loaded HDL lipoproteins during reverse cholesterol transport involves a series of enzymes, transporters in peripheral tissue, as well as other apolipoproteins and lipoproteins. These extensive modifications and interconversions are well defined. Here, we present the hypothesis that a similar process occurs within the blood brain barrier (BBB) via glia-secreted lipid-poor apoE particles undergoing remodelling to become mature central nervous system (CNS) lipoproteins. We further pose several pressing issues and future directions for the study of lipoproteins in the brain.
- 239Cramer, P. E.; Cirrito, J. R.; Wesson, D. W.; Lee, C. Y. D.; Karlo, J. C.; Zinn, A. E.; Casali, B. T.; Restivo, J. L.; Goebel, W. D.; James, M. J.; Brunden, K. R.; Wilson, D. A.; Landreth, G. E. ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models. Science 2012, 335 (6075), 1503– 1506, DOI: 10.1126/science.1217697[Crossref], [PubMed], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktFWksbY%253D&md5=da3768e6a1506dbf5ecc18ef718caaf5ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in Alzheimer's disease Mouse ModelsCramer, Paige E.; Cirrito, John R.; Wesson, Daniel W.; Lee, C. Y. Daniel; Karlo, J. Colleen; Zinn, Adriana E.; Casali, Brad T.; Restivo, Jessica L.; Goebel, Whitney D.; James, Michael J.; Brunden, Kurt R.; Wilson, Donald A.; Landreth, Gary E.Science (Washington, DC, United States) (2012), 335 (6075), 1503-1506CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Alzheimer's disease (AD) is assocd. with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of sol. Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 h. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiol. Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.
- 240Fitz, N. F.; Cronican, A. A.; Lefterov, I.; Koldamova, R. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924– c, DOI: 10.1126/science.1235809[Crossref], [PubMed], [CAS], Google Scholar240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFSrur8%253D&md5=89ae0ba70eb65eed90a2f6d636cc2169Comment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"Fitz, Nicholas F.; Cronican, Andrea A.; Lefterov, Iliya; Koldamova, RadosvetaScience (Washington, DC, United States) (2013), 340 (6135), 924CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 Feb. 2012) demonstrated in a mouse model for Alzheimer's disease (AD) that treatment of APP/PS1ΔE9 mice with bexarotene decreased Aβ pathol. and ameliorated memory deficits. The authors confirm the reversal of memory deficits in APP/PS1ΔE9 mice expressing human APOE3 or APOE4 to the levels of their nontransgenic controls and the significant decrease of interstitial fluid Aβ, but not the effects on amyloid deposition.
- 241Price, A. R.; Xu, G.; Siemienski, Z. B.; Smithson, L. A.; Borchelt, D. R.; Golde, T. E.; Felsenstein, K. M. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924– d, DOI: 10.1126/science.1234089[Crossref], [PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFSrur0%253D&md5=27a71a8aac1a8631bd12c252a1ba7fcfComment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"Price, Ashleigh R.; Xu, Guilian; Siemienski, Zoe B.; Smithson, Lisa A.; Borchelt, David R.; Golde, Todd E.; Felsenstein, Kevin M.Science (Washington, DC, United States) (2013), 340 (6135), 924CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 Feb. 2012) demonstrates short-term bexarotene treatment clearing preexisting β-amyloid deposits from the brains of APP/PS1ΔE9 mice with low amyloid burden, providing a rationale for repurposing this anticancer agent as an Alzheimer's disease (AD) therapeutic. Using a nearly identical treatment regimen, the authors were unable to detect any evidence of drug efficacy despite demonstration of target engagement.
- 242Tesseur, I.; Lo, A. C.; Roberfroid, A.; Dietvorst, S.; Van Broeck, B.; Borgers, M.; Gijsen, H.; Moechars, D.; Mercken, M.; Kemp, J.; D'Hooge, R.; De Strooper, B. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924-e, DOI: 10.1126/science.1233937
- 243Veeraraghavalu, K.; Zhang, C.; Miller, S.; Hefendehl, J. K.; Rajapaksha, T. W.; Ulrich, J.; Jucker, M.; Holtzman, D. M.; Tanzi, R. E.; Vassar, R.; Sisodia, S. S. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924– f, DOI: 10.1126/science.1235505[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFSrurY%253D&md5=c7014b2effed1f3cd1d7d7f194f3311cComment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"Veeraraghavalu, Karthikeyan; Zhang, Can; Miller, Sean; Hefendehl, Jasmin K.; Rajapaksha, Tharinda W.; Ulrich, Jason; Jucker, Mathias; Holtzman, David M.; Tanzi, Rudolph E.; Vassar, Robert; Sisodia, Sangram S.Science (Washington, DC, United States) (2013), 340 (6135), 924CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 Feb. 2012) reported that bexarotene rapidly reduces β-amyloid (Aβ) levels and plaque burden in two mouse models of Aβ deposition in Alzheimer's disease (AD). The authors now report that, although bexarotene reduces sol. Aβ40 levels in one of the mouse models, the drug has no impact on plaque burden in three strains that exhibit Aβ amyloidosis.
- 244Ghosal, K.; Haag, M.; Verghese, P. B.; West, T.; Veenstra, T.; Braunstein, J. B.; Bateman, R. J.; Holtzman, D. M.; Landreth, G. E. A Randomized Controlled Study to Evaluate the Effect of Bexarotene on Amyloid-β and Apolipoprotein E Metabolism in Healthy Subjects. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2016, 2 (2), 110– 120, DOI: 10.1016/j.trci.2016.06.001
- 245Cummings, J. L.; Zhong, K.; Kinney, J. W.; Heaney, C.; Moll-Tudla, J.; Joshi, A.; Pontecorvo, M.; Devous, M.; Tang, A.; Bena, J. Double-Blind, Placebo-Controlled, Proof-of-Concept Trial of Bexarotene in Moderate Alzheimer’s Disease. Alzheimer’s Res. Ther. 2016, 8 (4), 4, DOI: 10.1186/s13195-016-0173-2[Crossref], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXltlenu7o%253D&md5=810dcf97d13126caad88d099c50e7e48Double-blind, placebo-controlled, proof-of-concept trial of bexarotene in moderate Alzheimer's diseaseCummings, Jeffrey L.; Zhong, Kate; Kinney, Jefferson W.; Heaney, Chelcie; Moll-Tudla, Joanne; Joshi, Abhinay; Pontecorvo, Michael; Devous, Michael; Tang, Anne; Bena, JamesAlzheimer's Research & Therapy (2016), 8 (), 4/1-4/9CODEN: ARTLCD; ISSN:1758-9193. (BioMed Central Ltd.)Background: We assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer's disease (AD) in a proof-of-concept trial. Methods: Twenty patients with AD [Mini Mental State Examn. (MMSE) score 10-20 inclusive] with pos. florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 wk. The amyloid imaging result was the primary outcome. Whole-population analyses and prespecified analyses by genotype [apolipoprotein E ε4 (ApoE4) carriers and ApoE4 noncarriers] were conducted. Secondary outcomes included scores on the Alzheimer's Disease Assessment Scale-Cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living scale, MMSE, Clin. Dementia Rating scale, and Neuropsychiatric Inventory. Serum amyloid-β (Aβ) peptide sequences Aβ1-40 and Aβ1-42 measurements were collected as biomarker outcomes. Results: There was no change in the composite or regional amyloid burden when all patients were included in the anal. ApoE4 noncarriers showed a significant redn. in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was obsd. in ApoE4 carriers. There was a significant assocn. between increased serum Aβ1-42 and redns. in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clin. measure. Conclusions: The primary outcome of this trial was neg. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ1-42 in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies.
- 246Lammi, J.; Perlmann, T.; Aarnisalo, P. Corepressor Interaction Differentiates the Permissive and Non-Permissive Retinoid X Receptor Heterodimers. Arch. Biochem. Biophys. 2008, 472 (2), 105– 114, DOI: 10.1016/j.abb.2008.02.003[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXktVKgtrw%253D&md5=6e274e82f219e2964a5e731083fa0feaCorepressor interaction differentiates the permissive and non-permissive retinoid X receptor heterodimersLammi, Johanna; Perlmann, Thomas; Aarnisalo, PiiaArchives of Biochemistry and Biophysics (2008), 472 (2), 105-114CODEN: ABBIA4; ISSN:0003-9861. (Elsevier)Nurr1 is an orphan nuclear receptor regulating transcription both as a monomer and as a heterodimer with retinoid X receptor (RXR). RXR-Nurr1 heterodimers are permissive RXR heterodimers as they activate transcription in response to RXR ligands. In contrast, heterodimers formed by RXR and retinoic acid receptor (RAR) are non-permissive as they activate transcription only upon RAR ligand binding. We studied the mechanism mediating permissiveness and non-permissiveness by creating receptor chimeras between Nurr1 and RAR. We show that the amino-terminal part of the Nurr1 ligand binding domain conveys permissiveness to RXR-Nurr1 heterodimers. This region is involved in interactions with the corepressors SMRT and NcoR. The corepressors were released from RXR-Nurr1 heterodimers by RXR ligand binding. In contrast, RXR ligand increased the interaction between RXR-RAR heterodimers and the corepressors. The corepressors were released only upon binding of RAR ligand. In conclusion, corepressor interaction differentiates the permissive RXR-Nurr1 heterodimers from the non-permissive RXR-RAR heterodimers.
- 247Schrage, K.; Koopmans, G.; Joosten, E. A. J.; Mey, J. Macrophages and Neurons Are Targets of Retinoic Acid Signaling after Spinal Cord Contusion Injury. Eur. J. Neurosci. 2006, 23 (2), 285– 295, DOI: 10.1111/j.1460-9568.2005.04534.x[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD287gslWksw%253D%253D&md5=6ec8f001cb10032cb3ba307e5118a846Macrophages and neurons are targets of retinoic acid signaling after spinal cord contusion injurySchrage Kirsten; Koopmans Guido; Joosten Elbert A J; Mey JorgThe European journal of neuroscience (2006), 23 (2), 285-95 ISSN:0953-816X.The physiological reactions after spinal cord injury are accompanied by local synthesis of the transcriptional activator retinoic acid (RA). RA exerts its effects by binding to retinoic acid receptors (RAR) which heterodimerize with retinoid X receptors (RXR) and then act as ligand-activated transcription factors. To identify possible cellular targets of RA we investigated protein levels and cellular distribution of retinoid receptors in the rat spinal cord at 4, 7, 14 and 21 days after a contusion injury. In the nonlesioned spinal cord, immunoreactivity for RARalpha, RXRalpha, RXRbeta and RXRgamma was localized in the cytosol of neurons, that of RXRalpha and RXRbeta in astrocytes and that of RARalpha, RXRalpha and RXRgamma in some oligodendrocytes. After contusion injury RARalpha and all RXRs appeared in the cell nuclei of reactive microglia and macrophages. This nuclear staining began at 4 days, was most prominent at 7 and 14 days and had decreased at 21 days after injury. A similar nuclear translocation was also observed for the RARalpha, RXRalpha and RXRbeta staining in neurons situated around the border of the contusion. These observations suggest that RA participates as a signal for the physiological responses of microglia and neurons after CNS injury.
- 248Natrajan, M. S.; de la Fuente, A. G.; Crawford, A. H.; Linehan, E.; Nuñez, V.; Johnson, K. R.; Wu, T.; Fitzgerald, D. C.; Ricote, M.; Bielekova, B.; Franklin, R. J. M. Retinoid X Receptor Activation Reverses Age-Related Deficiencies in Myelin Debris Phagocytosis and Remyelination. Brain 2015, 138 (12), 3581– 3597, DOI: 10.1093/brain/awv289[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28zhs12nsw%253D%253D&md5=11739816fdc564568296b576d38b5eafRetinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelinationNatrajan Muktha S; de la Fuente Alerie G; Crawford Abbe H; Franklin Robin J M; Linehan Eimear; Fitzgerald Denise C; Nunez Vanessa; Ricote Mercedes; Johnson Kory R; Wu Tianxia; Bielekova BibianaBrain : a journal of neurology (2015), 138 (Pt 12), 3581-97 ISSN:.The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.
- 249Baer, A. S.; Syed, Y. A.; Kang, S. U.; Mitteregger, D.; Vig, R.; Ffrench-Constant, C.; Franklin, R. J. M.; Altmann, F.; Lubec, G.; Kotter, M. R. Myelin-Mediated Inhibition of Oligodendrocyte Precursor Differentiation Can Be Overcome by Pharmacological Modulation of Fyn-RhoA and Protein Kinase C Signalling. Brain 2009, 132 (2), 465– 481, DOI: 10.1093/brain/awn334[Crossref], [PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M7jt1KlsA%253D%253D&md5=ef148293bfbc13fedf5bef6ff286154eMyelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signallingBaer Alexandra S; Syed Yasir A; Kang Sung Ung; Mitteregger Dieter; Vig Raluca; Ffrench-Constant Charles; Franklin Robin J M; Altmann Friedrich; Lubec Gert; Kotter Mark RBrain : a journal of neurology (2009), 132 (Pt 2), 465-81 ISSN:.Failure of oligodendrocyte precursor cell (OPC) differentiation contributes significantly to failed myelin sheath regeneration (remyelination) in chronic demyelinating diseases. Although the reasons for this failure are not completely understood, several lines of evidence point to factors present following demyelination that specifically inhibit differentiation of cells capable of generating remyelinating oligodendrocytes. We have previously demonstrated that myelin debris generated by demyelination inhibits remyelination by inhibiting OPC differentiation and that the inhibitory effects are associated with myelin proteins. In the present study, we narrow down the spectrum of potential protein candidates by proteomic analysis of inhibitory protein fractions prepared by CM and HighQ column chromatography followed by BN/SDS/SDS-PAGE gel separation using Nano-HPLC-ESI-Q-TOF mass spectrometry. We show that the inhibitory effects on OPC differentiation mediated by myelin are regulated by Fyn-RhoA-ROCK signalling as well as by modulation of protein kinase C (PKC) signalling. We demonstrate that pharmacological or siRNA-mediated inhibition of RhoA-ROCK-II and/or PKC signalling can induce OPC differentiation in the presence of myelin. Our results, which provide a mechanistic link between myelin, a mediator of OPC differentiation inhibition associated with demyelinating pathologies and specific signalling pathways amenable to pharmacological manipulation, are therefore of significant potential value for future strategies aimed at enhancing CNS remyelination.
- 250Kotter, M. R.; Zhao, C.; van Rooijen, N.; Franklin, R. J.M. Macrophage-Depletion Induced Impairment of Experimental CNS Remyelination Is Associated with a Reduced Oligodendrocyte Progenitor Cell Response and Altered Growth Factor Expression. Neurobiol. Dis. 2005, 18 (1), 166– 175, DOI: 10.1016/j.nbd.2004.09.019[Crossref], [PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXkslOgtQ%253D%253D&md5=c4c544e09699e93b7c8082e2d9485aeeMacrophage depletion-induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expressionKotter, Mark R.; Zhao, Chao; van Rooijen, Nico; Franklin, Robin J. M.Neurobiology of Disease (2005), 18 (1), 166-175CODEN: NUDIEM; ISSN:0969-9961. (Elsevier)Although macrophages are mediators of CNS demyelination, they are also implicated in remyelination. To examine the role of macrophages in CNS remyelination, adult rats were depleted of monocytes using clodronate liposomes and demyelination induced in the spinal cord white matter using lysolecithin. In situ hybridization for scavenger receptor-B and myelin basic protein (MBP) revealed a transiently impaired macrophage response assocd. with delayed remyelination in liposome-treated animals. Macrophage redn. corresponded with delayed recruitment of PDGFRα+ oligodendrocyte progenitor cells (OPCs), which preceded changes in myelin phagocytosis, indicating a macrophage effect on OPCs independent of myelin debris clearance. Macrophage depletion-induced changes in the mRNA expression of insulin-like growth factor-1 and transforming growth factor β1, but not platelet-derived growth factor-A and fibroblast growth factor-2. Thus, the macrophage response to toxin-induced demyelination influences the growth factor environment, thereby affecting the behavior of OPCs and hence the efficiency of remyelination.
- 251Xu, J.; Drew, P. D. 9-Cis-Retinoic Acid Suppresses Inflammatory Responses of Microglia and Astrocytes. J. Neuroimmunol. 2006, 171 (1–2), 135– 144, DOI: 10.1016/j.jneuroim.2005.10.004[Crossref], [PubMed], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xkt1yi&md5=2661968b0cfe380b2a3cbf4c65352a0a9-Cis-retinoic acid suppresses inflammatory responses of microglia and astrocytesXu, Jihong; Drew, Paul D.Journal of Neuroimmunology (2006), 171 (1-2), 135-144CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)Retinoic acid (RA) regulates a wide range of biol. process, including inflammation. Previously, RA was shown to inhibit the clin. signs of exptl. autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The current study investigated the effects of 9-cis-RA on primary mouse microglia and astrocytes, two cell types implicated in the pathol. of MS and EAE. The studies demonstrated that 9-cis-RA inhibited the prodn. of nitric oxide (NO) as well as the pro-inflammatory cytokines TNF-α, IL-1β and IL-12 p40 by LPS-stimulated microglia. However, this retinoid had no effect on IL-6 secretion and increased MCP-1 prodn. by LPS-stimulated microglia. In LPS-stimulated astrocytes, 9-cis-RA inhibited NO and TNF-α prodn. but had not effect on IL-1β, IL-6 and MCP-1 secretion. These results suggest that RA modulates EAE, at least in part, by suppressing the prodn. of NO and specific inflammatory cytokines from activated glia and suggests that RA might be effective in the treatment of MS.
- 252Chandraratna, R. A.; Sanders, M. E. WO2017/075607 Treatment of Nervous System Disorders Using Combinations of RXR Agonists and Thyroid Hormones, IO Ther. INC, 2017.
- 253Volle, D. H. Nuclear Receptors as Pharmacological Targets, Where Are We Now?. Cell. Mol. Life Sci. 2016, 73 (10), 3777– 3780, DOI: 10.1007/s00018-016-2327-6[Crossref], [PubMed], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhtlalt77P&md5=f797c4ae6c54eb144c95ce13dbb6ca48Nuclear receptors as pharmacological targets, where are we now?Volle, David H.Cellular and Molecular Life Sciences (2016), 73 (20), 3777-3780CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Basel)Knowledge of integrative physiol. is a major challenge for scientists, as even small deregulation could lead to diseases. Cells communicate with each other to control many processes such as growth, migration, survival, or differentiation. Such interaction could be achieved via several mechanisms either through cell-cell interactions and/or through the signaling of mols. that bind to receptors on the membrane or in the target cells. The produced mols. could have either autocrine, paracrine stimulations, or even act on distant organs (endocrine signaling).
- 254Levin, A. A.; Sturzenbecker, L. J.; Kazmer, S.; Bosakowski, T.; Huselton, C.; Allenby, G.; Speck, J.; Kratzeisen, C.; Rosenberger, M.; Lovey, A.; Grippo, J. F. 9-Cis Retinoic Acid Stereoisomer Binds and Activates the Nuclear Receptor RXR Alpha. Nature 1992, 355 (6358), 359– 361, DOI: 10.1038/355359a0[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XhtVSisL0%253D&md5=b9e901de55bf245c7459cfde7cc6b63a9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRαLevin, Arthur A.; Sturzenbecker, Laurie J.; Kazmer, Sonja; Bosakowski, Thomas; Huselton, Christine; Allenby, Gary; Speck, Jeffrey; Kratzeisen, C.; Rosenberger, Michael; et al.Nature (London, United Kingdom) (1992), 355 (6358), 359-61CODEN: NATUAS; ISSN:0028-0836.The activity of retinoids is thought to be mediated by interactions with 2 subfamilies of nuclear retinoic acid receptors, RAR and RXR. The RARs bind all-trans retinoic acid (t-RA) with high affinity and alter gene expression as a consequence of this direct ligand interaction. RXRα is activated by t-RA, yet has little binding affinity for this ligand. t-RA may be converted to a more proximate ligand that directly binds and activates RXRα, and a method of nuclear receptor-dependent ligand trapping was developed to test this hypothesis. A stereoisomer of retinoic acid, 9-cis retinoic acid, which directly binds and activates RXRα was identified. These results suggest a new role for isomerization in the physiol. of natural retinoids.
- 255Goldstein, J. T.; Dobrzyn, A.; Clagett-Dame, M.; Pike, J. W.; Deluca, H. F. Isolation and Characterization of Unsaturated Fatty Acids as Natural Ligands for the Retinoid-X Receptor. Arch. Biochem. Biophys. 2003, 420 (1), 185– 193, DOI: 10.1016/j.abb.2003.09.034[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXovVWgtb8%253D&md5=d64099a06d2497c3d9769ce26cdb53acIsolation and characterization of unsaturated fatty acids as natural ligands for the retinoid-X receptorGoldstein, Jonathan T.; Dobrzyn, Agnieszka; Clagett-Dame, Margaret; Pike, J. Wesley; DeLuca, Hector F.Archives of Biochemistry and Biophysics (2003), 420 (1), 185-193CODEN: ABBIA4; ISSN:0003-9861. (Elsevier Science)The retinoid-X receptor (RXR) is a ligand activated nuclear receptor that is the heterodimer partner for many class II nuclear receptors. Previously identified natural ligands for this receptor include 9-cis retinoic acid (9cRA), docosahexaenoic acid, and phytanic acid. Our studies were performed to det. if there are any unidentified, physiol. important RXR ligands. Agonists for RXR were purified from rat heart and testes lipid exts. with the use of a cell-based reporter assay to monitor RXR activation. Purified active fractions contained a variety of unsatd. fatty acids and components were quantified by gas-liq. chromatog. of derivatized samples. The corresponding fatty acid stds. elicited a similar response in the reporter cell assay. Competition binding anal. revealed that the active fatty acids compete with [3H]9cRA for binding to RXR. Non-esterified fatty acids were analyzed from lipid exts. of isolated heart and testes nuclei and endogenous concns. were found to be within the range of their detd. binding affinities. Our studies reveal tissue dependent profiles of RXR agonists and support the idea of unsatd. fatty acids as physiol. ligands of RXR.
- 256Fitzgerald, P.; Teng, M.; Chandraratna, R. A. S.; Heyman, A.; Allegretto, A. Retinoic Acid Receptor α Expression Correlates with Retinoid-Induced Growth Inhibition of Human Breast Cancer Cells Regardless of Estrogen Receptor Status. Cancer Res. 1997, 57 (13), 2642– 2650[PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2szkvFSltQ%253D%253D&md5=b890df47f31d129e5ae7a395c5b5801eRetinoic acid receptor alpha expression correlates with retinoid-induced growth inhibition of human breast cancer cells regardless of estrogen receptor statusFitzgerald P; Teng M; Chandraratna R A; Heyman R A; Allegretto E ACancer research (1997), 57 (13), 2642-50 ISSN:0008-5472.Retinoic acid receptor (RAR) alpha has been shown to play a role in retinoid-induced growth inhibition of human breast cancer cell lines that express the estrogen receptor (ER). The dogma in the field has been that ER-positive breast cancer cell lines respond to retinoid treatment because they express RAR alpha, whereas ER-negative breast cancer cell lines are refractory to retinoid treatment and have been thought to express little or no RAR alpha. We set out to test several ER-negative breast cancer cell lines for expression of RAR alpha protein and responsiveness to retinoids in growth inhibition assays. Of six ER-negative breast cancer cell lines that were tested, one (SK-BR-3) had high levels of RAR alpha protein as measured by ligand-binding immunoprecipitation (approximately 55 fmol/mg protein) and also displayed sensitivity to growth inhibition by retinoids (9-cis-retinoic acid; EC50, approximately 3 nM). These cells were more sensitive than an ER-positive cell line, T-47D, which expressed approximately 35 fmol RAR alpha/mg total protein (9-cis retinoic acid; EC50, approximately 50-100 nM). Another ER-negative cell line, Hs578T, also expressed RAR alpha (approximately 23 fmol/mg) and was sensitive to retinoid-induced growth inhibition, albeit to a lesser extent than SK-BR-3 or T-47D cells. In contrast, the other ER-negative cell lines tested expressed low (<10 fmol/mg) or no detectable levels of RAR alpha protein and also did not respond to retinoids in growth inhibition assays. A RAR alpha agonist displayed 100 times greater potency than a RARgamma agonist in growth inhibition of both T-47D and SK-BR-3 cells, suggesting RAR alpha involvement in the process. Furthermore, a RAR alpha antagonist completely abolished the growth inhibition induced by RAR agonists, implying that the activity of the agonists is exerted solely through RAR alpha, not RARgamma, which is also expressed in both cell lines. Additionally, although retinoid X receptor (RXR) compounds are weakly active in growth inhibition of the RAR alpha-positive cell lines, they markedly increased the growth-inhibitory activity of RAR ligands. RXR compounds also potentiated the action of the antiestrogen 4-hydroxytamoxifen to inhibit the growth of T-47D cells. These findings have clinical ramifications in that patients with ER-negative tumors that are RAR alpha positive may be candidates for retinoid therapy. Additionally, combinations of RXR ligands with RAR ligands (especially RAR alpha agonists) and/or antiestrogens may have utility in the treatment of breast cancer.
- 257Vuligonda, V.; Thacher, S. M.; Chandraratna, R. A. Enantioselective Syntheses of Potent Retinoid X Receptor Ligands: Differential Biological Activities of Individual Antipodes. J. Med. Chem. 2001, 44 (14), 2298– 2303, DOI: 10.1021/jm0100584[ACS Full Text], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXktFamt7Y%253D&md5=3447f09b74c8ed27806b868dfd0422a2Enantioselective Syntheses of Potent Retinoid X Receptor Ligands: Differential Biological Activities of Individual AntipodesVuligonda, Vidyasagar; Thacher, Scott M.; Chandraratna, Roshantha A. S.Journal of Medicinal Chemistry (2001), 44 (14), 2298-2303CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis and characterization of chiral retinoid X receptor (RXR) selective ligands are described. The enantiomeric acids I and II were synthesized employing an enantioselective cyclopropanation procedure as the key step. Compd. I, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any retinoic acid receptor (RAR) activity. The R,R enantiomer II is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of I was further confirmed in a hyperglycemic animal model (db/db mice). Compd. I lowered glucose by 50% by day 7 at 2 mg/kg, whereas II had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
- 258Boehm, M. F.; McClurg, M. R.; Pathirana, C.; Mangelsdorf, D.; White, S. K.; Hebert, J.; Winn, D.; Goldman, M. E.; Heyman, R. A. Synthesis of High Specific Activity [3H]-9-Cis-Retinoic Acid and Its Application for Identifying Retinoids with Unusual Binding Properties. J. Med. Chem. 1994, 37 (3), 408– 414, DOI: 10.1021/jm00029a013[ACS Full Text], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXjt1eru7g%253D&md5=5fc66f91aa7f4a7f49c42588b1087272Synthesis of high specific activity tritium-labeled [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding propertiesBoehm, Marcus F.; McClurg, Michael R.; Pathirana, Charles; Mangelsdorf, David; White, Steven K.; Hebert, Jonathan; Winn, David; Goldman, Mark E.; Heyman, Richard A.Journal of Medicinal Chemistry (1994), 37 (3), 408-14CODEN: JMCMAR; ISSN:0022-2623.All-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an addnl. endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biol. role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, the authors report the synthesis of high specific activity [3H]-9-cis-RA (I) and its application to study the ligand-binding properties of the various retinoid receptor subtypes. The authors examd. the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.
- 259Blair, H. A.; Scott, L. J. Alitretinoin : A Review in Severe Chronic Hand Eczema. Drugs 2016, 76 (13), 1271– 1279, DOI: 10.1007/s40265-016-0621-0[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s3is1emsA%253D%253D&md5=7b91f59707edd401724e10f40c753947Alitretinoin: A Review in Severe Chronic Hand EczemaBlair Hannah A; Scott Lesley JDrugs (2016), 76 (13), 1271-1279 ISSN:.Chronic hand eczema is a common but frequently disabling skin condition which poses a significant social and economic burden. Although skin protection measures and topical therapies are fundamental in its management, some patients are refractory to first-line therapy with topical corticosteroids and require systemic treatment. Alitretinoin (9-cis-retinoic acid; Toctino(®)) is an endogenous vitamin A derivative with high binding affinity for both retinoic acid receptors and retinoid X receptors. Alitretinoin is the first systemic treatment to be approved in the EU for use in patients with severe chronic hand eczema unresponsive to potent topical corticosteroids. This article updates an earlier review of alitretinoin in this indication, focusing on recently published data. In clinical trials, treatment with alitretinoin 10 or 30 mg once daily for up to 24 weeks improved the severity and extent of severe chronic hand eczema in adults, with significantly more alitretinoin than placebo recipients achieving ratings of 'clear' or 'almost clear' hands on the Physician Global Impression of Change scale. For the most part, data obtained in real-world studies were consistent with those observed in clinical trials. Alitretinoin was generally well tolerated, with most adverse events being reversible, dose-dependent and of mild or moderate severity. Thus, oral alitretinoin is a useful treatment option for patients with severe chronic hand eczema unresponsive to potent topical corticosteroids.
- 260Cheer, S. M.; Foster, R. H. Alitretinoin. Am. J. Clin. Dermatol. 2000, 1 (5), 307– 314, DOI: 10.2165/00128071-200001050-00005[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MnltVCitw%253D%253D&md5=830a8d9c36f42f0638a5c43ccc10c40fAlitretinoinCheer S M; Foster R HAmerican journal of clinical dermatology (2000), 1 (5), 307-14; discussion 315-6 ISSN:1175-0561.Alitretinoin is a retinoid receptor pan-agonist, which has been investigated in the treatment of Kaposi's sarcoma (KS). Binding with high affinity to all known retinoid receptors, alitretinoin is thought to regulate proliferation, differentiation, and apoptosis of KS cells. Significantly more patients experienced complete or partial responses [according to the AIDS Clinical Trials Group (ACTG) criteria for topical treatment of cutaneous KS] with alitretinoin 0.1% gel 2 to 4 times daily than with vehicle gel in 2 phase III, multicenter, 12-week, randomized, double-blind clinical trials of patients with AIDS-related KS (35 vs 18%, p = 0.002 and 37 vs 7%, p = 0.00003, respectively). Responses were also observed in patients refractory to prior systemic or topical anti-KS therapies. In an intent-to-treat analysis in a phase II trial, 37% of patients with AIDS-related KS receiving alitretinoin capsules 60 to 100 mg/m2/day demonstrated either complete or partial responses (determined by ACTG criteria). The majority of adverse events associated with alitretinoin 0.1% gel were classified as either mild or moderate, occurred at the site of application and were reversible. In both phase III trials, rash was the most common adverse event. The most common adverse events in patients taking alitretinoin capsules included headache, dry skin, rash, alopecia, exfoliative dermatitis, and hyperlipidemia.
- 261Son, J. H.; Park, S. Y.; Cho, Y. S.; Byun, Y. S.; Chung, B. Y.; Cho, H. J.; Kim, H. O.; Park, C. W. Two Cases of Successful Treatment of Refractory Chronic Inflammatory Skin Disease, Atopic Dermatitis and Psoriasis with Oral Alitretinoin. Ann. Dermatol. 2017, 29 (4), 503– 506, DOI: 10.5021/ad.2017.29.4.503[Crossref], [PubMed], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cfivFSiug%253D%253D&md5=9c6599e56467da05879d28475a5fe8b0Two Cases of Successful Treatment of Refractory Chronic Inflammatory Skin Disease, Atopic Dermatitis and Psoriasis with Oral AlitretinoinSon Jee Hee; Park Sook Young; Cho Yong Se; Byun Yun Sun; Chung Bo Young; Kim Hye One; Park Chun Wook; Cho Hee JinAnnals of dermatology (2017), 29 (4), 503-506 ISSN:1013-9087.There is no expanded citation for this reference.
- 262Rühl, R.; Krzyzosiak, A.; Niewiadomska-Cimicka, A.; Rochel, N.; Szeles, L.; Vaz, B.; Wietrzych-Schindler, M.; Álvarez, S.; Szklenar, M.; Nagy, L.; de Lera, A. R.; Krezel, W. 9-Cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice. PLoS Genet. 2015, 11 (6), e1005213, DOI: 10.1371/journal.pgen.1005213
- 263de Lera, Á.; Krezel, W.; Rühl, R. An Endogenous Mammalian Retinoid X Receptor Ligand, at Last!. ChemMedChem 2016, 11 (10), 1027– 1037, DOI: 10.1002/cmdc.201600105[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntlSrtbo%253D&md5=d3f6d42cfedcd86ff2b8ac57062a51f4An Endogenous Mammalian Retinoid X Receptor Ligand, At Last!de Lera, Angel R.; Krezel, Wojciech; Ruehl, RalphChemMedChem (2016), 11 (10), 1027-1037CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)9-Cis-Retinoic acid was identified and claimed to be the endogenous ligand of the retinoid X receptors (RXRs) in 1992. Since then, the endogenous presence of this compd. has never been rigorously confirmed. Instead, concerns have been raised by other groups that have reported that 9-cis-retinoic acid is undetectable or that its presence occurs at very low levels. Furthermore, these low levels could not satisfactorily explain the physiol. activation of RXR. Alternative ligands, among them various lipids, have also been identified, but also did not fulfill criteria for rigorous endogenous relevance, and their consideration as bona fide endogenous mammalian RXR ligand has likewise been questioned. Recently, novel studies claim that the satd. analog 9-cis-13,14-dihydroretinoic acid functions as an endogenous physiol. relevant mammalian RXR ligand.
- 264Neuringer, M.; Anderson, G. J.; Connor, W. E. The Essentiality of N-3 Fatty Acids for the Development and Function of the Retina and Brain. Annu. Rev. Nutr. 1988, 8, 517– 541, DOI: 10.1146/annurev.nu.08.070188.002505[Crossref], [PubMed], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXlsVyhur8%253D&md5=b1a666895515541a6a60cff4933528ceThe essentiality of n-3 fatty acids for the development and function of the retina and brainNeuringer, Martha; Anderson, Gregory J.; Connor, William E.Annual Review of Nutrition (1988), 8 (), 517-41CODEN: ARNTD8; ISSN:0199-9885.A review, with 170 refs., on the tissue distribution of n-3 fatty acids, their accumulation during development, their dietary deficiency, and their functional effects in biol. membranes.
- 265Bourguet, W.; Vivat, V.; Wurtz, J.-M.; Chambon, P.; Gronemeyer, H.; Moras, D. Crystal Structure of a Heterodimeric Complex of RAR and RXR Ligand-Binding Domains. Mol. Cell 2000, 5 (2), 289– 298, DOI: 10.1016/S1097-2765(00)80424-4[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhslyhtLw%253D&md5=5cb4369df1bd81d12151749e128c626bCrystal structure of a heterodimeric complex of RAR and RXR ligand-binding domainsBourguet, William; Vivat, Valerie; Wurtz, Jean-Marie; Chambon, Pierre; Gronemeyer, Hinrich; Moras, DinoMolecular Cell (2000), 5 (2), 289-298CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)The crystal structure of a heterodimer between the ligand-binding domains (LBDs) of the human RARα bound to a selective antagonist and the constitutively active mouse RXRαF318A mutant shows that, pushed by a bulky extension of the ligand, RARα helix H12 adopts an antagonist position. The unexpected presence of a fatty acid in the ligand-binding pocket of RXRαF318A is likely to account for its apparent "constitutivity.". Specific conformational changes suggest the structural basis of pure and partial antagonism. The RAR-RXR heterodimer interface is similar to that obsd. in most nuclear receptor (NR) homodimers. A correlative anal. of 3D structures and sequences provides a novel view on dimerization among members of the nuclear receptor superfamily.
- 266Heald, P.; Mehlmauer, M.; Martin, A. G.; Crowley, C. A.; Yocum, R. C.; Reich, S. D. Topical Bexarotene Therapy for Patients with Refractory or Persistent Early-Stage Cutaneous T-Cell Lymphoma: Results of the Phase III Clinical Trial. J. Am. Acad. Dermatol. 2003, 49 (5), 801– 815, DOI: 10.1016/S0190-9622(03)01475-0[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3svpvV2rsw%253D%253D&md5=0bf3c93a5ca34df3c0eb5f01c908c19cTopical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trialHeald Peter; Mehlmauer Marilyn; Martin Ann G; Crowley Constance A; Yocum Richard C; Reich Steven DJournal of the American Academy of Dermatology (2003), 49 (5), 801-15 ISSN:0190-9622.OBJECTIVES: We sought to determine the safety and efficacy of topical bexarotene (Targretin; Ligand Pharmaceuticals, La Jolla, Calif) gel 1% in patients with refractory or persistent early-stage cutaneous T-cell lymphoma. METHODS: We conducted a multinational, open-label, phase III study of 50 patients with stage IA to IIA cutaneous T-cell lymphoma. The primary end point classification was the overall complete and partial response rate by the higher of 2 measures: the Physician's Global Assessment of Clinical Condition or the Composite Assessment of Index Lesion Disease Severity. RESULTS: The overall response rates for the Physician's Global Assessment of Clinical Condition, Composite Assessment of Index Lesion Disease Severity, and primary end point classification were 44%, 46%, and 54%, respectively. The most common adverse events possibly related to study medication were mild to moderate irritant dermatitis, pruritus, pain (ie, primarily burning at application site), and skin disorder (eg, skin inflammation, excoriation, and new lesions). There were no serious treatment-related adverse events. CONCLUSIONS: Topical bexarotene gel was generally well tolerated and demonstrated substantial efficacy in patients with refractory or persistent early-stage cutaneous T-cell lymphoma.
- 267Wong, S. F. Oral Bexarotene in the Treatment of Cutaneous T-Cell Lymphoma. Ann. Pharmacother. 2001, 35 (9), 1056– 1065, DOI: 10.1345/aph.10223[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXntlajtL8%253D&md5=8b2a41ac4a91eb75bef26c0f752dcaa2Oral bexarotene in the treatment of cutaneous T-cell lymphomaWong, Siu-FunAnnals of Pharmacotherapy (2001), 35 (9), 1056-1065CODEN: APHRER; ISSN:1060-0280. (Harvey Whitney Books Co.)A review. Objective: To review the preclin. and clin. information related to oral bexarotene approved by the Food and Drug Administration for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy. Data Sources: Literature accessed through MEDLINE (from 1990 to July 2000) and provided by the manufacturer. Key search terms included bexarotene, Targretin, LGD1069, and cutaneous T-cell lymphoma. Data Synthesis: The management of CTCL remains controversial due to its rarity in the US and its heterogeneity. An evaluation focusing on the pharmacol. of bexarotene and its role in the management of the different stages of CTCL was conducted. Conclusions: Bexarotene has demonstrated activity in the treatment of CTCL. The oral route of administration and the adverse effect profile of bexarotene appear to make this drug a favorable option for the treatment of CTCL compared with other systemic therapies. Phase III randomized studies are needed to det. the clin. benefits of bexarotene as monotherapy or combination therapy in the treatment of CTCL.
- 268Boehm, M. F.; Zhang, L.; Badea, B. A.; White, S. K.; Mais, D. E.; Berger, E.; Suto, C. M.; Goldman, M. E.; Heyman, R. A. Synthesis and Structure-Activity Relationships of Novel Retinoid X Receptor-Selective Retinoids. J. Med. Chem. 1994, 37 (18), 2930– 2941, DOI: 10.1021/jm00044a014[ACS Full Text], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmsFKjt7g%253D&md5=90003c75aa4fd4934ad3aeb0773119f2Synthesis and Structure-Activity Relationships of Novel Retinoid X Receptor-Selective RetinoidsBoehm, Marcus F.; Zhang, Lin; Badea, Beth Ann; White, Steven K.; Mais, Dale E.; Berger, Elaine; Suto, Carla M.; Goldman, Mark E.; Heyman, Richard A.Journal of Medicinal Chemistry (1994), 37 (18), 2930-41CODEN: JMCMAR; ISSN:0022-2623.Two series of potent retinoid X receptor (RXR)-selective compds. were designed and synthesized based upon recent observation that(E)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl]benzoic acid binds and transactivates only the retinoic acid receptor (RAR) subtypes whereas its 3-Me deriv. binds and transactivates both the RAR and RXR subfamilies. Functional groups in the 3-position of the tetrahydronaphthalenes I [R = H, alkyl, halo, OH, OMe; X = O, CH2] results in compds. which elicit potent and selective activation of the RXR class. Such RXR-selective compds. offer pharmacol. tools for elucidating the biol. role of the individual retinoid receptors with which they interact. Activation profiles in cotransfection and competitive binding assays as well as mol. modeling calcns. demonstrate crit. structural determinants that confer selectivity for members of the RXR subfamily. The most potent compd. of these series, I [R = Me, X = CH2], is the first RXR-selective retinoid (designated as LGD1069) to enter clin. trials for cancer indications.
- 269Howell, S. R.; Shirley, M. A.; Grese, T. A.; Neel, D. A.; Wells, K. E.; Ulm, E. H. Bexarotene Metabolism in Rat, Dog, and Human, Synthesis of Oxidative Metabolites, and in Vitro Activity at Retinoid Receptors. Drug Metab. Dispos. 2001, 29 (7), 990– 998[PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXksFCntrg%253D&md5=b25bdaa09d196f1c09f2db869b0b2be2Bexarotene metabolism in rat, dog, and human, synthesis of oxidative metabolites, and in vitro activity at retinoid receptorsHowell, Stanley R.; Shirley, Michael A.; Grese, Timothy A.; Neel, David A.; Wells, Kirk E.; Ulm, Edgar H.Drug Metabolism and Disposition (2001), 29 (7), 990-998CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)The metab. of bexarotene, a rexinoid recently approved in the United States for treatment of cutaneous T-cell lymphoma, was studied using liver slices from untreated rats and dogs, liver microsomes from untreated and pretreated rats, and pooled human liver microsomes. Metabolite profiles were examd. in bile and plasma from rats and dogs, and plasma from humans treated with bexarotene. Four metabolites, racemic 6-hydroxy-bexarotene, racemic 7-hydroxy-bexarotene, 6-oxo-bexarotene, and 7-oxo-bexarotene, were synthesized and their binding to, and transactivation of retinoid receptors were examd. Qual. similar metabolite profiles were obsd. in the microsomal and liver slice exts.; the predominant metabolites were 6-hydroxy-bexarotene and glucuronides of parent or hydroxylated metabolites. Pretreatment of rats with bexarotene induced hepatic microsomal bexarotene metab. The hydroxy and oxo metabolites were obsd. in plasma of rats, dogs, and humans treated with bexarotene and 6-hydroxy-bexarotene was a major circulating metabolite. The oxidative metabolites were more abundant relative to parent in plasma from humans than from rat or dog. The predominant biliary metabolites in rat and dog were bexarotene acyl glucuronide and a glucuronide of oxidized bexarotene, resp. Since bexarotene elimination is primarily biliary in these species, these metabolites represent the main bexarotene metabolites in rats and dogs. The binding of synthetic metabolites to retinoid receptors was much reduced relative to parent compd. The metabolites exhibited minimal activity in transactivating retinoic acid receptors and had reduced activity at retinoid X receptors relative to bexarotene. Thus, while there is substantial systemic exposure to the oxidative metabolites of bexarotene, they are unlikely to elicit significant retinoid receptor activation following bexarotene administration.
- 270Wang, Y.; Rong, J.; Zhang, J.; Liu, Y.; Meng, X.; Guo, H.; Liu, H.; Chen, L. Morphology, in Vivo Distribution and Antitumor Activity of Bexarotene Nanocrystals in Lung Cancer. Drug Dev. Ind. Pharm. 2017, 43 (1), 132– 141, DOI: 10.1080/03639045.2016.1225752[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVGjs7zO&md5=cf1605f1fa77229dc3fc9046d51fa36dMorphology, in vivo distribution and antitumor activity of bexarotene nanocrystals in lung cancerWang, Yongjie; Rong, Jinghong; Zhang, Jiaozhen; Liu, Yu; Meng, Xuelian; Guo, Hejian; Liu, Hongsheng; Chen, LijiangDrug Development and Industrial Pharmacy (2017), 43 (1), 132-141CODEN: DDIPD8; ISSN:0363-9045. (Taylor & Francis Ltd.)The objective of this study was to develop and evaluate the morphol., biodistribution and antitumor activity of bexarotene nanocrystals delivery system. The morphol. was investigated using SEM (SEM), transmission electron microscopy (TEM), at. force microscope and bexarotene nanocrystals exhibited the advantages of making the efficacy more steady and durable compared with control group in lung with less cardiac accumulation as shown by biodistribution studies in vivo. In addn., MTT assay, flow cytometry anal., observation of morphol. changes and apoptotic body demonstrated that bexarotene nanocrystals could significantly enhance the in vitro cytotoxicity and induced G1 cycle arrest and apoptosis against A549 cells. Also, bexarotene nanocrystals had significant antitumor activity in mice bearing A549 cell line. This finding was correlated with both in vitro and in vivo. Thereby, the overall results suggest that the bexarotene nanocrystals represent a potential source of medicine, which made bexarotene nanocrystals a promising candidate for the treatment of lung cancer.
- 271Lowenthal, J.; Hull, S. C.; Pearson, S. D. The Ethics of Early Evidence - Preparing for a Possible Breakthrough in Alzheimer’s Disease. N. Engl. J. Med. 2012, 367 (6), 488– 490, DOI: 10.1056/NEJMp1203104[Crossref], [PubMed], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1SisrbO&md5=21302b88d829c904ca3d99634bbfe808The ethics of early evidence - preparing for a possible breakthrough in Alzheimer's diseaseLowenthal, Justin; Hull, Sara Chandros; Pearson, Steven D.New England Journal of Medicine (2012), 367 (6), 488-490CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)There is no expanded citation for this reference.
- 272Takamatsu, K.; Takano, A.; Yakushiji, N.; Morishita, K.; Matsuura, N.; Makishima, M.; Ali, H. I.; Akaho, E.; Tai, A.; Sasaki, K.; Kakuta, H. Reduction of Lipophilicity at the Lipophilic Domain of RXR Agonists Enables Production of Subtype Preference: RXRa- Preferential Agonist Possessing a Sulfonamide Moiety. ChemMedChem 2008, 3 (3), 454– 460, DOI: 10.1002/cmdc.200700265[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXlt1Krtbw%253D&md5=6487ff09cac2861d3877f8d6f8179aa2Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXRα-preferential agonist possessing a sulfonamide moietyTakamatsu, Kayo; Takano, Atsushi; Yakushiji, Nobumasa; Morishita, Ken-ichi; Matsuura, Nobuyasu; Makishima, Makoto; Ali, Hamed Ismail; Akaho, Eiichi; Tai, Akihiro; Sasaki, Kenji; Kakuta, HirokiChemMedChem (2008), 3 (3), 454-460CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Retinoid X receptor agonists (RXR agonists, rexinoids) are interesting candidates for the treatment of cancers such as tamoxifen-resistant breast cancer and taxol-resistant lung cancer. However, well-known RXR agonists possess a strong lipophilic character. In addn., although RXR has three subtypes, no subtype-selective RXR agonists are known. Thus the authors aimed to produce less-lipophilic and subtype-selective RXR agonists. By designing sulfonamide-type RXR agonists, compd. (I) was found to prefer RXRα over RXRβ and RXRγ, although the potency is less than the potencies of well-known RXR pan-agonists. Moreover, the results suggest that the redn. of lipophilicity at the hydrophobic interaction region of RXR agonists enables prodn. of RXR subtype preference. The finding will be useful for the creation of more potent and less-lipophilic subtype-selective RXR agonists aimed at the redn. of undesirable side effects.
- 273Boehm, M. F.; Zhang, L.; Zhi, L.; McClurg, M. R.; Berger, E.; Wagoner, M.; Mais, D. E.; Suto, C. M.; Davies, P. J. A.; Heyman, R. A.; Nadzan, A. M. Design and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia Cells. J. Med. Chem. 1995, 38 (16), 3146– 3155, DOI: 10.1021/jm00016a018[ACS Full Text], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmvF2htLg%253D&md5=c9bcc1f2449517cf62406151376cceddDesign and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia CellsBoehm, Marcus F.; Zhang, Lin; Zhi, Lin; McClurg, Michael R.; Berger, Elain; Wagoner, Murriel; Mais, Dale E.; Suto, Carla M.; Davies, Peter J. A.; et al.Journal of Medicinal Chemistry (1995), 38 (16), 3146-55CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structural modifications of the retinoid X receptor (RXR) selective compd. 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clin. trials for cancer and dermatol. indications, have resulted in the identification of increasingly potent retinoids with >1000-fold selectivity for the RXRs. The prepn. of a series of RXR selective retinoids as well as the biol. data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity are reported. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl]nicotinic acid (I, LG100268). This compd. has proven useful for investigating RXR-dependent biol. pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. These studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
- 274Takamatsu, K.; Takano, A.; Yakushiji, N.; Morohashi, K.; Morishita, K.; Matsuura, N.; Makishima, M.; Tai, A.; Sasaki, K.; Kakuta, H. The First Potent Subtype-Selective Retinoid X Receptor (RXR) Agonist Possessing a 3-Isopropoxy-4-isopropylphenylamino Moiety, NEt-3IP (RXRα/B-dual Agonist). ChemMedChem 2008, 3 (5), 780– 787, DOI: 10.1002/cmdc.200700313[Crossref], [PubMed], [CAS], Google Scholar275https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXms1emt7k%253D&md5=3ffe22aaa4a60aa23c7c3cb06da04a7cThe first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRα/β-dual agonist)Takamatsu, Kayo; Takano, Atsushi; Yakushiji, Nobumasa; Morohashi, Kazunori; Morishita, Kenichi; Matsuura, Nobuyasu; Makishima, Makoto; Tai, Akihiro; Sasaki, Kenji; Kakuta, HirokiChemMedChem (2008), 3 (5), 780-787CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Retinoid X receptor (RXR) agonists (rexinoids) are attracting much attention for their use in treatment of cancers, including tamoxifen-resistant breast cancer and taxol-resistant lung cancer, and metabolic disease. However, known RXR agonists have a highly lipophilic character. In addn., no subtype-selective RXR agonists have been found. The authors previously reported an RXRα-preferential agonist 4-[N-methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) amino]benzoic acid. The RXR agonistic activity is much less than that of well-known RXR agonists. To develop potent, less-lipophilic, and subtype-selective RXR agonists, the authors created new RXR agonists possessing alkoxy and iso-Pr groups as a lipophilic domain of the common structure of well-known RXR agonists. As a result, compds. possessing branched alkoxy groups (I) and (II), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, I was the first RXRα/β-selective (or RXRα/β-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP I is expected to become a new drug candidate and to be a useful biol. tool for clarifying each RXR subtype function.
- 275Pollinger, J.; Merk, D. Therapeutic Applications of the Versatile Fatty Acid Mimetic WY14643. Expert Opin. Ther. Pat. 2017, 27 (4), 517– 525, DOI: 10.1080/13543776.2017.1272578[Crossref], [PubMed], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFGhsbfO&md5=62cad45d760d76b2eb7b6ed1914a627bTherapeutic applications of the versatile fatty acid mimetic WY14643Pollinger, Julius; Merk, DanielExpert Opinion on Therapeutic Patents (2017), 27 (4), 517-525CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)A review. WY14643 - also known as pirinixic acid - is a versatile fatty acid mimetic that was originally developed as lipid lowering agent without knowledge of its mol. target. Various later studies discovered somewhat promiscuous activity of the compd. on several receptors and enzymes. Pirinixic acid though never having reached clin. use was subjected to many in vivo studies and exerted beneficial effects in a variety of disease models. Inventions claiming the use of WY14643 for numerous indications ranging from the originally intended application in metabolic dysbalances over cancer and inflammation to some rare syndromes have been evaluated. It is rather unlikely that pirinixic acid will gain relevance in treatment of metabolic diseases for which it was originally developed because more efficient and selective alternatives are available. Instead, several other claimed activities of the compd. e.g. in inflammation, neurodegeneration and cancer seem very promising. However, some of the underlying studies are biased and for some effects of pirinixic acid, the mol. target and mode of action remain to be identified.
- 276Watanabe, M.; Kakuta, H. Retinoid X Receptor Antagonists. Int. J. Mol. Sci. 2018, 19 (8), 2354 DOI: 10.3390/ijms19082354[Crossref], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnsVGiur4%253D&md5=89cdc1e936636de5b823f2da539c46e7Retinoid X receptor antagonistsWatanabe, Masaki; Kakuta, HirokiInternational Journal of Molecular Sciences (2018), 19 (8), 2354/1-2354/20CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)Retinoid X receptor (RXR) antagonists are not only useful as chem. tools for biol. research, but are also candidate drugs for the treatment of various diseases, including diabetes and allergies, although no RXR antagonist has yet been approved for clin. use. In this review, we present a brief overview of RXR structure, function, and target genes, and describe currently available RXR antagonists, their structural classification, and their evaluation, focusing on the latest research.
- 277Nakayama, M.; Yamada, S.; Ohsawa, F.; Ohta, Y.; Kawata, K.; Makishima, M.; Kakuta, H. Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB. ACS Med. Chem. Lett. 2011, 2 (12), 896– 900, DOI: 10.1021/ml200197e[ACS Full Text], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1Cqt77P&md5=2c88b7f5940b3763e4fe6708ce8bdc76Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IBNakayama, Mariko; Yamada, Shoya; Ohsawa, Fuminori; Ohta, Yui; Kawata, Kohei; Makishima, Makoto; Kakuta, HirokiACS Medicinal Chemistry Letters (2011), 2 (12), 896-900CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We discovered a potent retinoid X receptor (RXR) antagonist, 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(E)-styrylphenyl)amino]nicotinic acid (13e), that is structurally closely related to the RXR full agonist 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB) (4). Compd. 13e was synthesized via a simple route from 11 (I), a Me ester precursor of 4. Because 11 possesses high electrophilic reactivity because of the amino and alkoxy groups, it was readily transformed to 12 by iodization, and the iodine atom of 12 was converted to a C-C or C-N bond by means of palladium-catalyzed reaction to afford 13. Transcriptional activation assay revealed that 13g (in which the iodine atom was replaced with an amino group) is a weak RXR agonist, while 13d (a Ph group), 13e (a styryl group), and 13f (an anilino group) are RXR antagonists. Among them, 13e was found to be more potent than the known RXR antagonist PA452 (9).
- 278Merk, D.; Grisoni, F.; Friedrich, L.; Gelzinyte, E.; Schneider, G. Computer-Assisted Discovery of Retinoid X Receptor Modulating Natural Products and Isofunctional Mimetics. J. Med. Chem. 2018, 61 (12), 5442– 5447, DOI: 10.1021/acs.jmedchem.8b00494[ACS Full Text], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFWqt7zI&md5=7212ea553c1af55042265bf8862dc810Computer-Assisted Discovery of Retinoid X Receptor Modulating Natural Products and Isofunctional MimeticsMerk, Daniel; Grisoni, Francesca; Friedrich, Lukas; Gelzinyte, Elena; Schneider, GisbertJournal of Medicinal Chemistry (2018), 61 (12), 5442-5447CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Natural products (NPs) are progressively recognized as invaluable source of pharmacol. tools and lead structures. To enable NP-inspired retinoid X receptor (RXR) modulator design, three novel RXR-targeting NPs were computationally identified. Among them, valerenic acid was found to be selective for RXRβ, rendering it a unique pharmacol. tool compd. The NPs then served as templates for automated, ligand-based de novo design of innovative, easily accessible mimetics that inherited the biol. activities of their natural templates.
- 279Merk, D.; Grisoni, F.; Friedrich, L.; Gelzinyte, E.; Schneider, G. Scaffold Hopping from Synthetic RXR Modulators by Virtual Screening and de Novo Design. MedChemComm 2018, 9, 1289– 1292, DOI: 10.1039/C8MD00134K[Crossref], [PubMed], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVyjsrnO&md5=acb1eb5302706281d1c0ac7091a6b00bScaffold hopping from synthetic RXR modulators by virtual screening and de novo designMerk, Daniel; Grisoni, Francesca; Friedrich, Lukas; Gelzinyte, Elena; Schneider, GisbertMedChemComm (2018), 9 (8), 1289-1292CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)The lack of potent subtype-selective modulators of retinoid X receptors (RXRs) has hindered their full exploitation as promising drug targets. Using computational similarity searching, target prediction and automated de novo design, we identified novel RXR ligands exhibiting innovative mol. frameworks, pronounced receptor-subtype preference and suitable properties for hit-to-lead expansion.
- 280Pollinger, J.; Schierle, S.; Gellrich, L.; Ohrndorf, J.; Kaiser, A.; Heitel, P.; Chaikuad, A.; Knapp, S.; Merk, D. A Novel Biphenyl-Based Chemotype of Retinoid X Receptor Ligands Enables Subtype and Heterodimer Preferences. ACS Med. Chem. Lett. 2019, 10 (9), 1346– 1352, DOI: 10.1021/acsmedchemlett.9b00306[ACS Full Text], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFyrur%252FI&md5=68f55cb08fb121a37bbb61f3b2a7ff15A novel biphenyl-based chemotype of retinoid X receptor ligands enables subtype and heterodimer preferencesPollinger, Julius; Schierle, Simone; Gellrich, Leonie; Ohrndorf, Julia; Kaiser, Astrid; Heitel, Pascal; Chaikuad, Apirat; Knapp, Stefan; Merk, DanielACS Medicinal Chemistry Letters (2019), 10 (9), 1346-1352CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The nuclear retinoid X receptors (RXRs) are key ligand sensing transcription factors that serve as universal nuclear receptor heterodimer partners and are thus involved in numerous physiol. processes. Therapeutic targeting of RXRs holds high potential but available RXR activators suffer from limited safety. Selectivity for RXR subtypes or for certain RXR heterodimers are promising strategies for safer RXR modulation. Here, we report systematic structure-activity relationship studies on biphenyl carboxylates as new RXR ligand chemotype. We discovered specific structural modifications that enhance potency on RXRs, govern subtype preference, and vary modulation of different RXR heterodimers. Fusion of these structural motifs enabled specific tuning of subtype preferential profiles with markedly improved potency. Our results provide further evidence that RXR subtype selective ligands can be designed and present a novel chemotype of RXR modulators that can be tuned for subtype and heterodimer preferences.
- 281Islam, M. M.; Zhang, C.-L. TLX: A Master Regulator for Neural Stem Cell Maintenance and Neurogenesis. Biochim. Biophys. Acta, Gene Regul. Mech. 2015, 1849 (2), 210– 216, DOI: 10.1016/j.bbagrm.2014.06.001[Crossref], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Ohsr4%253D&md5=338813cbf592613401b5e0fd0171ea70TLX: A master regulator for neural stem cell maintenance and neurogenesisIslam, Mohammed M.; Zhang, Chun-LiBiochimica et Biophysica Acta, Gene Regulatory Mechanisms (2015), 1849 (2), 210-216CODEN: BBAGC6; ISSN:1874-9399. (Elsevier B.V.)A review. The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests that the misregulation of TLX might play a role in the onset and progression of human neurol. disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
- 282Shi, Y.; Lie, D. C.; Taupin, P.; Nakashima, K.; Ray, J.; Yu, R. T.; Gage, F. H.; Evans, R. M. Expression and Function of Orphan Nuclear Receptor TLX in Adult Neural Stem Cells. Nature 2004, 427 (6969), 78– 83, DOI: 10.1038/nature02211[Crossref], [PubMed], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhtVWhurrJ&md5=4ac248ea71ec56a6c9f43f53c09cc029Expression and function of orphan nuclear receptor TLX in adult neural stem cellsShi, Yanhong; Lie, D. Chichung; Taupin, Philippe; Nakashima, Kinichi; Ray, Jasodhara; Yu, Ruth T.; Gage, Fred H.; Evans, Ronald M.Nature (London, United Kingdom) (2004), 427 (6969), 78-83CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)The finding of neurogenesis in the adult brain led to the discovery of adult neural stem cells. TLX was initially identified as an orphan nuclear receptor expressed in vertebrate forebrains and is highly expressed in the adult brain. The brains of TLX-null mice have been reported to have no obvious defects during embryogenesis; however, mature mice suffer from retinopathies, severe limbic defects, aggressiveness, reduced copulation and progressively violent behavior. Here we show that TLX maintains adult neural stem cells in an undifferentiated, proliferative state. We show that TLX-expressing cells isolated by fluorescence-activated cell sorting (FACS) from adult brains can proliferate, self-renew and differentiate into all neural cell types in vitro. By contrast, TLX-null cells isolated from adult mutant brains fail to proliferate. Reintroducing TLX into FACS-sorted TLX-null cells rescues their ability to proliferate and to self-renew. In vivo, TLX mutant mice show a loss of cell proliferation and reduced labeling of nestin in neurogenic areas in the adult brain. TLX can silence glia-specific expression of the astrocyte marker GFAP in neural stem cells, suggesting that transcriptional repression may be crucial in maintaining the undifferentiated state of these cells.
- 283Miyawaki, T.; Uemura, A.; Dezawa, M.; Yu, R. T.; Ide, C.; Nishikawa, S.; Honda, Y.; Tanabe, Y.; Tanabe, T. Tlx, an Orphan Nuclear Receptor, Regulates Cell Numbers and Astrocyte Development in the Developing Retina. J. Neurosci. 2004, 24 (37), 8124– 8134, DOI: 10.1523/JNEUROSCI.2235-04.2004[Crossref], [PubMed], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXotVyisLg%253D&md5=37e674003cc27173173cff85cd071f68Tlx, an orphan nuclear receptor, regulates cell numbers and astrocyte development in the developing retinaMiyawaki, Takaya; Uemura, Akiyoshi; Dezawa, Mari; Yu, Ruth T.; Ide, Chizuka; Nishikawa, Shinichi; Honda, Yoshihito; Tanabe, Yasuto; Tanabe, TeruyoJournal of Neuroscience (2004), 24 (37), 8124-8134CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Tlx belongs to a class of orphan nuclear receptors that underlies many aspects of neural development in the CNS. However, the fundamental roles played by Tlx in the control of eye developmental programs remain elusive. By using Tlx knock-out (KO) mice, we show here that Tlx is expressed by retinal progenitor cells in the neuroblastic layer during the period of retinal layer formation, and it is crit. for controlling the generation of appropriate nos. of retinal progenies through the activities of cell cycle-related mols., cyclin D1 and p27Kip1. Tlx expression is restricted to Mueller cells in the mature retina and appears to control their proper development. Furthermore, we show that Tlx is expressed by immature astrocytes that migrate from the optic nerve onto the inner surface of the retina and is required for their generation and maturation, as assessed by honeycomb network formation and expression of R-cadherin, a crit. component for vasculogenesis. The impaired astrocyte network formation on the inner retinal surface is accompanied by the loss of vasculogenesis in Tlx KO retinas. Our studies thus indicate that Tlx underlies a fundamental developmental program of retinal organization and controls the generation of the proper nos. of retinal progenies and development of glial cells during the protracted period of retinogenesis.
- 284Monaghan, A. P.; Grau, E.; Bock, D.; Schütz, G. The Mouse Homolog of the Orphan Nuclear Receptor Tailless Is Expressed in the Developing Forebrain. Development 1995, 121 (3), 839– 853, DOI: 10.1242/dev.121.3.839[Crossref], [PubMed], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXksVCktLk%253D&md5=b30f03c84cbfbefe6204660259367032The mouse homolog of the orphan nuclear receptor tailless is expressed in the developing forebrainMonaghan, A. Paula; Grau, Evelyn; Bock, Dagmar; Schuetz, GuentherDevelopment (Cambridge, United Kingdom) (1995), 121 (3), 839-53CODEN: DEVPED; ISSN:0950-1991. (Company of Biologists)The Drosophila tailless gene is a member of the orphan nuclear receptor subfamily. In Drosophila, the tailless gene is required for pattern formation in embryonic poles. During development, tailless is activated in the termini of the embryo in response to the torso receptor tyrosine kinase signal transduction cascade. Recessive mutations of tailless result in abnormalities in anterior portions of the head and in all structures posterior to the eighth abdominal segment. Localized expression of tailless is required in combination with a second terminal gene, huckebein, to control the expression of downstream genes. The authors have isolated a mouse homolog of the Drosophila tailless gene, which shows considerable homol. in the DNA-binding domain suggesting that the resp. proteins bind similar recognition sequences. Although the ligand-binding domain shows features in common with the tailless ligand domain, it also shares conserved amino acid stretches with other orphan nuclear receptors, the human ovalbumin upstream binding protein transcription factors (hCOUP-TF I and II). The authors have analyzed the expression of tailless in mice, and show that it is specifically localized to the developing forebrain from day 8 p.c. and in dorsal midbrain from day 8.75 p.c. To define the anterior and posterior boundaries of expression, the authors compared the expression pattern of tailless to those of other forebrain markers, including distal-less (Dlx1), brain factor 1 (BF1), and the orthodenticle genes (Otx1 and Otx2). In addn. to the developing forebrain, these genes show dynamic patterns of expression in two structures whose development requires inductive signals from the forebrain: the eye and the nose. These results suggest that the mouse tailless gene may be required to pattern anterior brain differentiation.
- 285Li, S.; Sun, G.; Murai, K.; Ye, P.; Shi, Y. Characterization of TLX Expression in Neural Stem Cells and Progenitor Cells in Adult Brains. PLoS One 2012, 7 (8), e43324, DOI: 10.1371/journal.pone.0043324[Crossref], [PubMed], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlSjsrnI&md5=fc4b3d5642efc75c42ba30eb80277a39Characterization of TLX expression in neural stem cells and progenitor cells in adult brainsLi, Shengxiu; Sun, Guoqiang; Murai, Kiyohito; Ye, Peng; Shi, YanhongPLoS One (2012), 7 (8), e43324CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)TLX has been shown to play an important role in regulating the self-renewal and proliferation of neural stem cells in adult brains. However, the cellular distribution of endogenous TLX protein in adult brains remains to be elucidated. In this study, we used immunostaining with a TLX-specific antibody to show that TLX is expressed in both neural stem cells and transit-amplifying neural progenitor cells in the subventricular zone (SVZ) of adult mouse brains. Then, using a double thymidine analog labeling approach, we showed that almost all of the self-renewing neural stem cells expressed TLX. Interestingly, most of the TLX-pos. cells in the SVZ represented the thymidine analog-neg., relatively quiescent neural stem cell population. Using cell type markers and short-term BrdU labeling, we demonstrated that TLX was also expressed in the Mash1+ rapidly dividing type C cells. Furthermore, loss of TLX expression dramatically reduced BrdU label-retaining neural stem cells and the actively dividing neural progenitor cells in the SVZ, but substantially increased GFAP staining and extended GFAP processes. These results suggest that TLX is essential to maintain the self-renewing neural stem cells in the SVZ and that the GFAP+ cells in the SVZ lose neural stem cell property upon loss of TLX expression. Understanding the cellular distribution of TLX and its function in specific cell types may provide insights into the development of therapeutic tools for neurodegenerative diseases by targeting TLX in neural stem/progenitors cells.
- 286Benod, C.; Villagomez, R.; Webb, P. TLX: An Elusive Receptor. J. Steroid Biochem. Mol. Biol. 2016, 157, 41– 47, DOI: 10.1016/j.jsbmb.2015.11.001[Crossref], [PubMed], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVOqsb%252FP&md5=aec1c00da8a0e7d806852c6a223316baTLX: An elusive receptorBenod, Cindy; Villagomez, Rosa; Webb, PaulJournal of Steroid Biochemistry and Molecular Biology (2016), 157 (), 41-47CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)TLX (tailless receptor) is a member of the nuclear receptor superfamily and belongs to a class of nuclear receptors for which no endogenous or synthetic ligands have yet been identified. TLX is a promising therapeutic target in neurol. disorders and brain tumors. Thus, regulatory ligands for TLX need to be identified to complete the validation of TLX as a useful target and would serve as chem. probes to pursue the study of this receptor in disease models. It has recently been proved that TLX is druggable. However, to identify potent and specific TLX ligands with desirable biol. activity, a deeper understanding of where ligands bind, how they alter TLX conformation and of the mechanism by which TLX mediates the transcription of its target genes is needed. While TLX is in the process of escaping from orphanhood, future ligand design needs to progress in parallel with improved understanding of (i) the binding cavity or surfaces to target with small mols. on the TLX ligand binding domain and (ii) the nature of the TLX coregulators in particular cell and disease contexts. Both of these topics are discussed in this review.
- 287Yokoyama, A.; Takezawa, S.; Schule, R.; Kitagawa, H.; Kato, S. Transrepressive Function of TLX Requires the Histone Demethylase LSD1. Mol. Cell. Biol. 2008, 28 (12), 3995– 4003, DOI: 10.1128/MCB.02030-07[Crossref], [PubMed], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXntFanu74%253D&md5=a415eb96d627b7b5de33d2341ea578edTransrepressive function of TLX requires the histone demethylase LSD1Yokoyama, Atsushi; Takezawa, Shinichiro; Schule, Roland; Kitagawa, Hirochika; Kato, ShigeakiMolecular and Cellular Biology (2008), 28 (12), 3995-4003CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)TLX is an orphan nuclear receptor (also called NR2E1) that regulates the expression of target genes by functioning as a constitutive transrepressor. The physiol. significance of TLX in the cytodifferentiation of neural cells in the brain is known. However, the corepressors supporting the transrepressive function of TLX have yet to be identified. In this report, Y79 retinoblastoma cells were subjected to biochem. techniques to purify proteins that interact with TLX, and we identified LSD1 (also called KDM1), which appears to form a complex with CoREST and histone deacetylase 1. LSD1 interacted with TLX directly through its SWIRM and amine oxidase domains. LSD1 potentiated the transrepressive function of TLX through its histone demethylase activity as detd. by a luciferase assay using a genomically integrated reporter gene. LSD1 and TLX were recruited to a TLX-binding site in the PTEN gene promoter, accompanied by the demethylation of H3K4me2 and deacetylation of H3. Knockdown of either TLX or LSD1 derepressed expression of the endogenous PTEN gene and inhibited cell proliferation of Y79 cells. Thus, the present study suggests that LSD1 is a prime corepressor for TLX.
- 288Zhang, C.-L.; Zou, Y.; Yu, R. T.; Gage, F. H.; Evans, R. M. Nuclear Receptor TLX Prevents Retinal Dystrophy and Recruits the Corepressor Atrophin1. Genes Dev. 2006, 20 (10), 1308– 1320, DOI: 10.1101/gad.1413606[Crossref], [PubMed], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XltVyrtbk%253D&md5=29a9750b5ca0645efa9c27740e75f7e2Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin 1Zhang, Chun-Li; Zou, Yuhua; Yu, Ruth T.; Gage, Fred H.; Evans, Ronald M.Genes & Development (2006), 20 (10), 1308-1320CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)During mammalian embryogenesis, precise coordination of progenitor cell proliferation and differentiation is essential for proper organ size and function. The involvement of TLX (NR2E1), an orphan nuclear receptor, has been implicated in ocular development, as Tlx-/- mice exhibit visual impairment. Using genetic and biochem. approaches, we show that TLX modulates retinal progenitor cell proliferation and cell cycle re-entry by directly regulating the expression of Pten and its target cyclin D1. Addnl., TLX finely tunes the progenitor differentiation program by modulating the phospholipase C and mitogen-activated protein kinase (MAPK) pathways and the expression of an array of cell type-specific transcriptional regulators. Consequently, Tlx-/- mice have a dramatic redn. in retina thickness and enhanced generation of S-cones, and develop severe early onset retinal dystrophy. Furthermore, TLX interacts with atrophin 1 (Atn1), a corepressor that is involved in human neurodegenerative dentatorubral-pallidoluysian atrophy (DRPLA) and that is essential for development of multiple tissues. Together, these results reveal a mol. strategy by which an orphan nuclear receptor can precisely orchestrate tissue-specific proliferation and differentiation programs to prevent retinal malformation and degeneration.
- 289Estruch, S. B.; Buzón, V.; Carbó, L. R.; Schorova, L.; Lüders, J.; Estébanez-Perpiñá, E. The Oncoprotein BCL11A Binds to Orphan Nuclear Receptor TLX and Potentiates Its Transrepressive Function. PLoS One 2012, 7 (6), e37963, DOI: 10.1371/journal.pone.0037963[Crossref], [PubMed], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xos1ekt7o%253D&md5=aad222b770759704e8190a3a581e75e1The oncoprotein BCL11A binds to orphan nuclear receptor TLX and potentiates its transrepressive functionEstruch, Sara B.; Buzon, Victor; Carbo, Laia R.; Schorova, Lenka; Luders, Jens; Estebanez-Perpina, EvaPLoS One (2012), 7 (6), e37963CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Nuclear orphan receptor TLX (NR2E1) functions primarily as a transcriptional repressor and its pivotal role in brain development, glioblastoma, mental retardation and retinopathologies make it an attractive drug target. TLX is expressed in the neural stem cells (NSCs) of the subventricular zone and the hippocampus subgranular zone, regions with persistent neurogenesis in the adult brain, and functions as an essential regulator of NSCs maintenance and self-renewal. Little is known about the TLX social network of interactors and only few TLX coregulators are described. To identify and characterize novel TLX-binders and possible coregulators, we performed yeast-two-hybrid (Y2H) screens of a human adult brain cDNA library using different TLX constructs as baits. Our screens identified multiple clones of Atrophin-1 (ATN1), a previously described TLX interactor. In addn., we identified an interaction with the oncoprotein and zinc finger transcription factor BCL11A (CTIP1/Evi9), a key player in the hematopoietic system and in major blood-related malignancies. This interaction was validated by expression and coimmunopptn. in human cells. BCL11A potentiated the transrepressive function of TLX in an in vitro reporter gene assay. Our work suggests that BCL11A is a novel TLX coregulator that might be involved in TLX-dependent gene regulation in the brain.
- 290Sun, G.; Yu, R. T.; Evans, R. M.; Shi, Y. Orphan Nuclear Receptor TLX Recruits Histone Deacetylases to Repress Transcription and Regulate Neural Stem Cell Proliferation. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (39), 15282– 15287, DOI: 10.1073/pnas.0704089104[Crossref], [PubMed], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFWkurnK&md5=ad0573103a07c12737303107ce39df85Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferationSun, GuoQiang; Yu, Ruth T.; Evans, Ronald M.; Shi, YanhongProceedings of the National Academy of Sciences of the United States of America (2007), 104 (39), 15282-15287CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)TLX is a transcription factor that is essential for neural stem cell proliferation and self-renewal. However, the mol. mechanism of TLX-mediated neural stem cell proliferation and self-renewal is largely unknown. We show here that TLX recruits histone deacetylases (HDACs) to its downstream target genes to repress their transcription, which in turn regulates neural stem cell proliferation. TLX interacts with HDAC3 and HDAC5 in neural stem cells. The HDAC5-interaction domain was mapped to TLX residues 359-385, which contains a conserved nuclear receptor-coregulator interaction motif IXXLL. Both HDAC3 and HDAC5 have been shown to be recruited to the promoters of TLX target genes along with TLX in neural stem cells. Recruitment of HDACs led to transcriptional repression of TLX target genes, the cyclin-dependent kinase inhibitor, p21CIP1/WAF1(p21), and the tumor suppressor gene, pten. Either inhibition of HDAC activity or knockdown of HDAC expression led to marked induction of p21 and pten gene expression and dramatically reduced neural stem cell proliferation, suggesting that the TLX-interacting HDACs play an important role in neural stem cell proliferation. Moreover, expression of a TLX peptide contg. the minimal HDAC5 interaction domain disrupted the TLX-HDAC5 interaction. Disruption of this interaction led to significant induction of p21 and pten gene expression and to dramatic inhibition of neural stem cell proliferation. Taken together, these findings demonstrate a mechanism for neural stem cell proliferation through transcriptional repression of p21 and pten gene expression by TLX-HDAC interactions.
- 291Griffett, K.; Bedia-Diaz, G.; Hegazy, L.; de Vera, I. M. S.; Wanninayake, U. S.; Billon, C.; Koelblen, T.; Wilhelm, M. L.; Burris, T. P. The Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural Retinoids. Cell Chem. Biol. 2020, 27 (10), 1272– 1284, DOI: 10.1016/j.chembiol.2020.07.013[Crossref], [PubMed], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFGhtL7F&md5=1d97202ab3dca443b5c8c7fcf36ef13eThe Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural RetinoidsGriffett, Kristine; Bedia-Diaz, Gonzalo; Hegazy, Lamees; de Vera, Ian Mitchelle S.; Wanninayake, Udayanga S.; Billon, Cyrielle; Koelblen, Thomas; Wilhelm, McKenna L.; Burris, Thomas P.Cell Chemical Biology (2020), 27 (10), 1272-1284.e4CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)TLX is an orphan nuclear receptor that plays a crit. role in both embryonic and adult neurogenesis, as well in the pathogenesis of glioblastomas. TLX functions predominately as a transcriptional repressor, but no natural ligands or high-affinity synthetic ligands have been identified. Here, we describe the identification of natural and synthetic retinoids as functional ligands for TLX. We identified potent synthetic retinoids that directly bind to TLX and either activate or inhibit its transcriptional repressor activity. Furthermore, we identified all-trans and 11-cis retinaldehyde (retinal), retinoids that play an essential role in the visual cycle, as the preferential natural retinoids that bind to and modulate the function of TLX. Mol. dynamics simulations followed by mutational anal. provided insight into the mol. basis of retinoid binding to TLX. Our data support the validity of TLX as a target for development of therapeutics to treat cognitive disorders and/or glioblastomas.
- 292Benod, C.; Villagomez, R.; Filgueira, C. S.; Hwang, P. K.; Leonard, P. G.; Poncet-Montange, G.; Rajagopalan, S.; Fletterick, R. J.; Gustafsson, J.-Å.; Webb, P. The Human Orphan Nuclear Receptor Tailless (TLX, NR2E1) Is Druggable. PLoS One 2014, 9 (6), e99440, DOI: 10.1371/journal.pone.0099440[Crossref], [PubMed], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1antLzN&md5=2627261362125e6ad548c7aa5b2a1802The human orphan nuclear receptor tailless (TLX, NR2E1) is druggableBenod, Cindy; Villagomez, Rosa; Filgueira, Carly S.; Hwang, Peter K.; Leonard, Paul G.; Poncet-Montange, Guillaume; Rajagopalan, Senapathy; Fletterick, Robert J.; Gustafsson, Jan-Ake; Webb, PaulPLoS One (2014), 9 (6), e99440/1-e99440/13, 13 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Nuclear receptors (NRs) are an important group of ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of orphan NRs. Small mols. to target these orphan NRs will provide unique resources for uncovering regulatory systems that impact human health and to modulate these pathways with drugs. The orphan NR tailless (TLX, NR2E1), a transcriptional repressor, is a major player in neurogenesis and Neural Stem Cell (NSC) derived brain tumors. No chem. probes that modulate TLX activity are available, and it is not clear whether TLX is druggable. To assess TLX ligand binding capacity, we created homol. models of the TLX ligand binding domain (LBD). Results suggest that TLX belongs to an emerging class of NRs that lack LBD helixes α1 and α2 and that it has potential to form a large open ligand binding pocket (LBP). Using a medium throughput screening strategy, we investigated direct binding of 20,000 compds. to purified human TLX protein and verified interactions with a secondary (orthogonal) assay. We then assessed effects of verified binders on TLX activity using luciferase assays. As a result, we report identification of three compds. (ccrp1, ccrp2 and ccrp3) that bind to recombinant TLX protein with affinities in the high nanomolar to low micromolar range and enhance TLX transcriptional repressive activity. We conclude that TLX is druggable and propose that our lead compds. could serve as scaffolds to derive more potent ligands. While our ligands potentiate TLX repressive activity, the question of whether it is possible to develop ligands to de-repress TLX activity remains open.
- 293Zhi, X.; Zhou, X. E.; He, Y.; Searose-Xu, K.; Zhang, C.-L.; Tsai, C.-C.; Melcher, K.; Xu, H. E. Structural Basis for Corepressor Assembly by the Orphan Nuclear Receptor TLX. Genes Dev. 2015, 29 (4), 440– 450, DOI: 10.1101/gad.254904.114[Crossref], [PubMed], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkt1Sqt7g%253D&md5=b9d3267b46d4936a660860161f542160Structural basis for corepressor assembly by the orphan nuclear receptor TLXZhi, Xiaoyong; Zhou, X. Edward; He, Yuanzheng; Searose-Xu, Kelvin; Zhang, Chun-Li; Tsai, Chih-Cheng; Melcher, Karsten; Xu, H. EricGenes & Development (2015), 29 (4), 440-450CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conserved ALXXLXXY motif of the Atro box. Mutations that weaken the TLX-Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression.
- 294Tan, M. H. E.; Zhou, X. E.; Soon, F.-F.; Li, X.; Li, J.; Yong, E.-L.; Melcher, K.; Xu, H. E. The Crystal Structure of the Orphan Nuclear Receptor NR2E3/PNR Ligand Binding Domain Reveals a Dimeric Auto-Repressed Conformation. PLoS One 2013, 8 (9), e74359, DOI: 10.1371/journal.pone.0074359[Crossref], [PubMed], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsV2rurnK&md5=9add629d6a8e857eec883b8a5194b786The crystal structure of the orphan nuclear receptor NR2E3/PNR ligand binding domain reveals a dimeric auto-repressed conformationTan, M. H. Eileen; Zhou, X. Edward; Soon, Fen-Fen; Li, Xiaodan; Li, Jun; Yong, Eu-Leong; Melcher, Karsten; Xu, H. EricPLoS One (2013), 8 (9), e74359CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Photoreceptor-specific nuclear receptor (PNR, NR2E3) is a key transcriptional regulator of human photoreceptor differentiation and maintenance. Mutations in the NR2E3-encoding gene cause various retinal degenerations, including Enhanced S-cone syndrome, retinitis pigmentosa and Goldman-Favre disease. Although physiol. ligands have not been identified, it is believed that binding of small mol. agonists, receptor desumoylation and receptor heterodimerization may switch NR2E3 from a transcriptional repressor to an activator. While these features make NR2E3 a potential therapeutic target for the treatment of retinal diseases, there has been a clear lack of structural information for the receptor. Here, we report the crystal structure of the apo NR2E3 ligand binding domain (LBD) at 2.8 Å resoln. Apo NR2E3 functions as transcriptional repressor in cells and the structure of its LBD is in a dimeric auto-repressed conformation. In this conformation, the putative ligand binding pocket is filled with bulky hydrophobic residues and the activation-function-2 (AF2) helix occupies the canonical cofactor binding site. Mutations designed to disrupt either the AF2/cofactor-binding site interface or the dimer interface compromised the transcriptional repressor activity of this receptor. Together, these results reveal several conserved structural features shared by related orphan nuclear receptors, suggest that most disease-causing mutations affect the receptor's structural integrity and allowed us to model a putative active conformation that can accommodate small ligands in its pocket.
- 295Sablin, E. P.; Woods, A.; Krylova, I. N.; Hwang, P.; Ingraham, H. A.; Fletterick, R. J. The Structure of Corepressor Dax-1 Bound to Its Target Nuclear Receptor LRH-1. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (47), 18390– 18395, DOI: 10.1073/pnas.0808936105[Crossref], [PubMed], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVyhsrvJ&md5=a3c7dad13cfc5c9cc5d02e7fdded57d2The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1Sablin, Elena P.; Woods, April; Krylova, Irina N.; Hwang, Peter; Ingraham, Holly A.; Fletterick, Robert J.Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (47), 18390-18395, S18390/1-S18390/11CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The Dax-1 protein is an enigmatic nuclear receptor that lacks an expected DNA binding domain, yet functions as a potent corepressor of nuclear receptors. Here we report the structure of Dax-1 bound to one of its targets, liver receptor homolog 1 (LRH-1). Unexpectedly, Dax-1 binds to LRH-1 using a new module, a repressor helix built from a family conserved sequence motif, PCFXXLP. Mutations in this repressor helix that are linked with human endocrine disorders dissoc. the complex and attenuate Dax-1 function. The structure of the Dax-1:LRH-1 complex provides the mol. mechanism for the function of Dax-1 as a potent transcriptional repressor.
- 296Kandel, P.; Semerci, F.; Bajic, A.; Baluya, D.; Ma, L.; Chen, K.; Cao, A.; Phongmekhin, T.; Matinyan, N.; Choi, W.; Jiménez-Panizo, A.; Chamakuri, S.; Raji, I. O.; Chang, L.; Fuentes-Prior, P.; MacKenzie, K. R.; Benn, C. L.; Estébanez-Perpiñá, E.; Venken, K.; Moore, D. D.; Young, D. W.; Maletic-Savatic, M. Oleic Acid Triggers Hippocampal Neurogenesis by Binding to TLX/NR2E1. bioRxiv 2020, 2020.10.28.359810.
- 297Niu, W.; Zou, Y.; Shen, C.; Zhang, C.-L. Activation of Postnatal Neural Stem Cells Requires Nuclear Receptor TLX. J. Neurosci. 2011, 31 (39), 13816– 13828, DOI: 10.1523/JNEUROSCI.1038-11.2011[Crossref], [PubMed], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1ylu7rK&md5=7b1a575f1e1e085a288184f30482fa49Activation of postnatal neural stem cells requires nuclear receptor TLXNiu, Wenze; Zou, Yuhua; Shen, Cheng Cheng; Zhang, Chun-LiJournal of Neuroscience (2011), 31 (39), 13816-13828CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Neural stem cells (NSCs) continually produce new neurons in postnatal brains. However, the majority of these cells stay in a nondividing, inactive state. The mol. mechanism that is required for these cells to enter proliferation still remains largely unknown. Here, we show that nuclear receptor TLX (NR2E1) controls the activation status of postnatal NSCs in mice. Lineage tracing indicates that TLX-expressing cells give rise to both activated and inactive postnatal NSCs. Surprisingly, loss of TLX function does not result in spontaneous glial differentiation, but rather leads to a precipitous age-dependent increase of inactive cells with marker expression and radial morphol. for NSCs. These inactive cells are mispositioned throughout the granular cell layer of the dentate gyrus during development and can proliferate again after reintroduction of ectopic TLX. RNA-seq anal. of sorted NSCs revealed a TLX-dependent global expression signature, which includes the p53 signaling pathway. TLX regulates p21 expression in a p53-dependent manner, and acute removal of p53 can rescue the proliferation defect of TLX-null NSCs in culture. Together, these findings suggest that TLX acts as an essential regulator that ensures the proliferative ability of postnatal NSCs by controlling their activation through genetic interaction with p53 and other signaling pathways.
- 298Roy, K.; Kuznicki, K.; Wu, Q.; Sun, Z.; Bock, D.; Schutz, G.; Vranich, N.; Monaghan, A. P. The Tlx Gene Regulates the Timing of Neurogenesis in the Cortex. J. Neurosci. 2004, 24 (38), 8333– 8345, DOI: 10.1523/JNEUROSCI.1148-04.2004[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXotVyntLs%253D&md5=471431a11f3d96864a26644032d68a65The tlx gene regulates the timing of neurogenesis in the cortexRoy, Kristine; Kuznicki, Kathleen; Wu, Qiang; Sun, Zhuoxin; Bock, Dagmar; Schutz, Gunther; Vranich, Nancy; Monaghan, A. PaulaJournal of Neuroscience (2004), 24 (38), 8333-8345CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)The tailless (tlx) gene is a forebrain-restricted transcription factor. Tlx mutant animals exhibit a redn. in the size of the cerebral hemispheres and assocd. structures (Monaghan et al., 1997). Superficial cortical layers are specifically reduced, whereas deep layers are relatively unaltered (Land and Monaghan, 2003). To det. whether the adult laminar phenotype has a developmental etiol. and whether it is assocd. with a change in proliferation/differentiation decisions, we examd. the cell cycle and neurogenesis in the embryonic cortex. We found that there is a temporal and regional requirement for the Tlx protein in progenitor cells (PCs). Neurons prematurely differentiate at all rostrocaudal levels up to mid-neurogenesis in mutant animals. Heterozygote animals have an intermediate phenotype indicating there is a threshold requirement for Tlx in early cortical neurogenesis. Our studies indicate that PCs in the ventricular zone are sensitive to loss of Tlx in caudal regions only; however, PCs in the subventricular zone are altered at all rostrocaudal levels in tlx-deficient animals. Furthermore, we found that the cell cycle is shorter from embryonic day 9.5 in tlx-/- embryos. At mid-neurogenesis, the PC population becomes depleted, and late PCs have a longer cell cycle in tlx-deficient animals. Consequently, later generated structures, such as upper cortical layers, the dentate gyrus, and the olfactory bulbs, are severely reduced. These studies indicate that tlx is an essential intrinsic regulator in the decision to proliferate or differentiate in the developing forebrain.
- 299Shi, Y.; Sun, G.; Zhao, C.; Stewart, R. Neural Stem Cell Self-Renewal. Crit. Rev. Oncol. Hematol. 2008, 65 (1), 43– 53, DOI: 10.1016/j.critrevonc.2007.06.004[Crossref], [PubMed], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sjjt1CrtA%253D%253D&md5=62802c2db4d67b0d36d5a4a3e1cf1523Neural stem cell self-renewalShi Yanhong; Sun Guoqiang; Zhao Chunnian; Stewart RichardCritical reviews in oncology/hematology (2008), 65 (1), 43-53 ISSN:1040-8428.Two fundamental properties of stem cells are their ability to self-renew and to differentiate. Self-renewal is an integration of proliferation control with the maintenance of an undifferentiated state. Stem cell self-renewal is regulated by the dynamic interplay between transcription factors, epigenetic control, microRNA (miRNA) regulators, and cell-extrinsic signals from the microenvironment in which stem cells reside. Recent progress in defining specific roles for cell-intrinsic factors and extrinsic factors in regulating stem cell self-renewal starts to unfold the multilayered regulatory networks. This review focuses on cell-intrinsic regulators, including orphan nuclear receptor TLX, polycomb transcriptional repressor Bmi1, high-mobility-group DNA binding protein Sox2, basic helix-loop-helix Hes genes, histone modifying enzymes and chromatin remodeling proteins, and small RNA modulators, as well as cell-extrinsic signaling molecules, such as Wnt, Notch, Sonic hedgehog (Shh), TGFalpha, EGF, and FGF. Unraveling the mechanisms by which neural stem cells renew themselves will provide insights into both basic neurosciences and clinical applications of stem cell-based cell replacement therapies for neurodegenerative diseases.
- 300Elmi, M.; Matsumoto, Y.; Zeng, Z.; Lakshminarasimhan, P.; Yang, W.; Uemura, A.; Nishikawa, S.; Moshiri, A.; Tajima, N.; Agren, H.; Funa, K. TLX Activates MASH1 for Induction of Neuronal Lineage Commitment of Adult Hippocampal Neuroprogenitors. Mol. Cell. Neurosci. 2010, 45 (2), 121– 131, DOI: 10.1016/j.mcn.2010.06.003[Crossref], [PubMed], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVeht73K&md5=473e32be30770e18f63cb5af546be14bTLX activates MASH1 for induction of neuronal lineage commitment of adult hippocampal neuroprogenitorsElmi, Muna; Matsumoto, Yoshiki; Zeng, Zhao-jun; Lakshminarasimhan, Pavithra; Yang, Weiwen; Uemura, Akiyoshi; Nishikawa, Shin-ichi; Moshiri, Alicia; Tajima, Nobuyoshi; Aagren, Hans; Funa, KeikoMolecular and Cellular Neuroscience (2010), 45 (2), 121-131CODEN: MOCNED; ISSN:1044-7431. (Elsevier B.V.)The orphan nuclear receptor TLX has been proposed to act as a repressor of cell cycle inhibitors to maintain the neural stem cells in an undifferentiated state, and prevents commitment into astrocyte lineages. However, little is known about the mechanism of TLX in neuronal lineage commitment and differentiation. A majority of adult rat hippocampus-derived progenitors (AHPs) cultured in the presence of FGF express a high level of TLX and a fraction of these cells also express the proneural gene MASH1. Upon FGF withdrawal, TLX rapidly decreased, while MASH1 was intensely expressed within 1 h, decreasing gradually to disappear at 24 h. Adenoviral transduction of TLX in AHP cells in the absence of FGF transiently increased cell proliferation, however, later resulted in neuronal differentiation by inducing MASH1, Neurogenin1, DCX, and MAP2ab. Furthermore, TLX directly targets and activates the MASH1 promoter through interaction with Sp1, recruiting co-activators whereas dismissing the co-repressor HDAC4. Conversely, silencing of TLX in AHPs decreased β-III tubulin and DCX expression and promoted glial differentiation. Our results thus suggest that TLX not only acts as a repressor of cell cycle and glial differentiation but also activates neuronal lineage commitment in AHPs.
- 301Liu, H.-K.; Belz, T.; Bock, D.; Takacs, A.; Wu, H.; Lichter, P.; Chai, M.; Schütz, G. The Nuclear Receptor Tailless Is Required for Neurogenesis in the Adult Subventricular Zone. Genes Dev. 2008, 22 (18), 2473– 2478, DOI: 10.1101/gad.479308[Crossref], [PubMed], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1ClsbjO&md5=2ef11ad47ec1b056f811bef13ca816f4The nuclear receptor tailless is required for neurogenesis in the adult subventricular zoneLiu, Hai-Kun; Belz, Thorsten; Bock, Dagmar; Takacs, Andrea; Wu, Hui; Lichter, Peter; Chai, Minqiang; Schuetz, GuentherGenes & Development (2008), 22 (18), 2473-2478CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)The tailless (Tlx) gene encodes an orphan nuclear receptor that is expressed by neural stem/progenitor cells in the adult brain of the subventricular zone (SVZ) and the dentate gyrus (DG). The function of Tlx in neural stem cells of the adult SVZ remains largely unknown. We show here that in the SVZ of the adult brain Tlx is exclusively expressed in astrocyte-like B cells. An inducible mutation of the Tlx gene in the adult brain leads to complete loss of SVZ neurogenesis. Furthermore, anal. indicates that Tlx is required for the transition from radial glial cells to astrocyte-like neural stem cells. These findings demonstrate the crucial role of Tlx in the generation and maintenance of NSCs in the adult SVZ in vivo.
- 302Monaghan, A. P.; Bock, D.; Gass, P.; Schwger, A.; Wolfer, D. P.; Lipp, H.-P.; Schütz, G. Defective Limbic System in Mice Lacking the Tailless Gene. Nature 1997, 390 (6659), 515– 517, DOI: 10.1038/37364[Crossref], [PubMed], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXnvF2nsrY%253D&md5=b67b720676987ff4c0fa44f5c9a530d8Defective limbic system in mice lacking the tailless geneMonaghan, A. P.; Bock, D.; Gass, P.; Schwager, A.; Wolfer, D. P.; Lipp, H.-P.; Schhutz, G.Nature (London) (1997), 390 (6659), 515-517CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)The gene tailless is a member of the superfamily of genes that encode transcription factors of the ligand-activated nuclear receptor type, and is expressed in the invertebrate and vertebrate brain. In mice, it transcripts are restricted to the periventricular zone of the forebrain, the site or origin of neurons and glia. Here we use homologous recombination to generate mice that lack a functional tailless protein. Homozygous mutant mice are viable at birth, indicating that tailless is not required for prenatal survival; however, adult mutant mice show a redn. in the size of rhinencephalic and limbic structures, including the olfactory infrarhinal and entorhinal cortex, amygdala and dentate gyrus. Both male and female mice are more aggressive than usual and females lack normal maternal instincts. These animals therefore enable a mol. approach to be taken towards understanding the genetic architecture and morphogenesis of the forebrain.
- 303Yu, R. T.; Chiang, M.-Y.; Tanabe, T.; Kobayashi, M.; Yasuda, K.; Evans, R. M.; Umesono, K. The Orphan Nuclear Receptor Tlx Regulates Pax2 and Is Essential for Vision. Proc. Natl. Acad. Sci. U. S. A. 2000, 97 (6), 2621– 2625, DOI: 10.1073/pnas.050566897[Crossref], [PubMed], [CAS], Google Scholar307https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXitVaiu7k%253D&md5=0f0f465d337c9b00400131713e1622c9The orphan nuclear receptor Tlx regulates Pax2 and is essential for visionYu, Ruth T.; Chiang, Ming-Yi; Tanabe, Teruyo; Kobayashi, Mime; Yasuda, Kunio; Evans, Ronald M.; Umesono, KazuhikoProceedings of the National Academy of Sciences of the United States of America (2000), 97 (6), 2621-2625CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Although the development of the vertebrate eye is well described, the no. of transcription factors known to be key to this process is still limited. The localized expression of the orphan nuclear receptor Tlx in the optic cup and discrete parts of the central nervous system suggested the possible role of Tlx in the formation or function of these structures. Analyses of Tlx targeted mice revealed that, in addn. to the central nervous system cortical defects, lack of Tlx function results in progressive retinal and optic nerve degeneration with assocd. blindness. An extensive screen of Tlx-pos. and Tlx-neg. P19 neural precursors identified Pax2 as a candidate target gene. This identification is significant, because Pax2 is known to be involved in retinal development in both the human and the mouse eye. We find that Pax2 is a direct target and that the Tlx binding site in its promoter is conserved between mouse and human. These studies show that Tlx is a key component of retinal development and vision and an upstream regulator of the Pax2 signaling cascade.
- 304Juárez, P.; Valdovinos, M. G.; May, M. E.; Lloyd, B. P.; Couppis, M. H.; Kennedy, C. H. Serotonin2A/C Receptors Mediate the Aggressive Phenotype of TLX Gene Knockout Mice. Behav. Brain Res. 2013, 256, 354– 361, DOI: 10.1016/j.bbr.2013.07.044[Crossref], [PubMed], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsleiurzM&md5=bb753288cca15b41caf69ddd7da1c1c9Serotonin2A/C receptors mediate the aggressive phenotype of TLX gene knockout miceJuarez, Pablo; Valdovinos, Maria G.; May, Michael E.; Lloyd, Blair P.; Couppis, Maria H.; Kennedy, Craig H.Behavioural Brain Research (2013), 256 (), 354-361CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)Deleting the tailless TLX gene in mice produces a highly aggressive phenotype yet to be characterized in terms of heterozygous animals or neurotransmitter mechanisms. We sought to establish pharmacol. control over aggression and study the role of serotonin 5-HT 2A/C receptors in mediating changes in aggression. We analyzed aggression in mice heterozygous +/- or homozygous -/- for the TLX gene and wild-types +/+ using a resident-intruder paradigm. No +/+ mice were aggressive, 36 fx of +/- TLX and 100 fx of -/- TLX mice showed aggression. Dose-effect functions were established for clozapine 0.1-1.5 mg/kg, i.p., ketanserin 0.3-1.25 mg/kg, i.p., and ±-1-2,5-dimethoxy-4-iodophenyl-2-aminopropane ± DOI| 0.5-2.0 mg/kg, i.p. Injecting clozapine decreased the frequency and duration of attacks for +/- TLX and -/- TLX mice. Clozapine did not decrease grooming in either +/- TLX or -/- TLX mice but may have increased locomotion for -/- TLX mice. Injecting ketanserin, a 5-HT2A/C receptor antagonist, produced differential decreases in frequency and latency to aggression between genotypes and corresponding increases in locomotor behavior. Injecting ± DOI, a 5-HT2A/C receptor agonist, increased the frequency and duration of attacks, decreased the latency to attacks, and decreased locomotion in +/- and -/- TLX mice. Results of the current study suggest aggression displayed by TLX null and heterozygous mice involves 5-HT2A/C receptors.
- 305Murai, K.; Qu, Q.; Sun, G.; Ye, P.; Li, W.; Asuelime, G.; Sun, E.; Tsai, G. E.; Shi, Y. Nuclear Receptor TLX Stimulates Hippocampal Neurogenesis and Enhances Learning and Memory in a Transgenic Mouse Model. Proc. Natl. Acad. Sci. U. S. A. 2014, 111 (25), 9115– 9120, DOI: 10.1073/pnas.1406779111[Crossref], [PubMed], [CAS], Google Scholar309https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpsVKjt7s%253D&md5=3e1045115a97490d8ad5341273468df8Nuclear receptor TLX stimulates hippocampal neurogenesis and enhances learning and memory in a transgenic mouse modelMurai, Kiyohito; Qu, Qiuhao; Sun, GuoQiang; Ye, Peng; Li, Wendong; Asuelime, Grace; Sun, Emily; Tsai, Guochuan E.; Shi, YanhongProceedings of the National Academy of Sciences of the United States of America (2014), 111 (25), 9115-9120CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased nos. of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the nos. of BrdU+ cells and BrdU+NeuN+ neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong assocn. between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory.
- 306O’Leary, J. D.; Kozareva, D. A.; Hueston, C. M.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. The Nuclear Receptor Tlx Regulates Motor, Cognitive and Anxiety-Related Behaviours during Adolescence and Adulthood. Behav. Brain Res. 2016, 306, 36– 47, DOI: 10.1016/j.bbr.2016.03.022[Crossref], [PubMed], [CAS], Google Scholar310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xks1yiurw%253D&md5=1b9ec138b713c67c7ffa7cb2f09b24d8The nuclear receptor Tlx regulates motor, cognitive and anxiety-related behaviours during adolescence and adulthoodO'Leary, James D.; Kozareva, Danka A.; Hueston, Cara M.; O'Leary, Olivia F.; Cryan, John F.; Nolan, Yvonne M.Behavioural Brain Research (2016), 306 (), 36-47CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)The nuclear receptor Tlx is a key regulator of embryonic and adult hippocampal neurogenesis and has been genetically linked to bipolar disorder. Mice lacking Tlx (Nr2e1-/-) display deficits in adult hippocampal neurogenesis and behavioral abnormalities. However, whether Tlx regulates behavior during adolescence or in a sex-dependent manner remains unexplored. Therefore, we investigated the role of Tlx in a series of behavioral tasks in adolescent male and female mice with a spontaneous deletion of Tlx (Nr2e1-/- mice). Testing commenced at adolescence (postnatal day 28) and continued until adulthood (postnatal day 67). Adolescent male and female Nr2e1-/- mice were hyperactive in an open field, an effect that persisted in adulthood. Male but not female Nr2e1-/- mice exhibited reduced thigmotaxis during adolescence and adulthood. Impairments in rotarod motor performance developed in male and female Nr2e1-/- mice at the onset of adulthood. Spontaneous alternation in the Y-maze, a hippocampus-dependent task, was impaired in adolescent but not adult male and female Nr2e1-/- mice. Contextual fear conditioning was impaired in adolescent male Nr2e1-/- mice only, but both male and female adolescent Nr2e1-/- mice showed impaired cued fear conditioning, a hippocampal-amygdala dependent cognitive process. These deficits persisted into adulthood in males but not females. In conclusion, deletion of Tlx impairs motor, cognitive and anxiety-related behaviors during adolescence and adulthood in male and female mice with most effects occurring during adolescence rather than adulthood, independent of housing conditions. This suggests that Tlx has functions beyond regulation of adult hippocampal neurogenesis, and may be an important target in understanding neurobiol. disorders.
- 307Kozareva, D. A.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. Deletion of TLX and Social Isolation Impairs Exercise-Induced Neurogenesis in the Adolescent Hippocampus. Hippocampus 2018, 28 (1), 3– 11, DOI: 10.1002/hipo.22805[Crossref], [PubMed], [CAS], Google Scholar311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Sitw%253D%253D&md5=1d99b0ba3b31824e2449ecdfcedf7b4bDeletion of TLX and social isolation impairs exercise-induced neurogenesis in the adolescent hippocampusKozareva, Danka A.; O'Leary, Olivia F.; Cryan, John F.; Nolan, Yvonne M.Hippocampus (2018), 28 (1), 3-11CODEN: HIPPEL; ISSN:1050-9631. (Wiley-Blackwell)Adolescence is a sensitive period of neurodevelopment during which life experiences can have profound effects on the brain. Hippocampal neurogenesis, the neurodevelopmental process of generating functional new neurons from neural stem cells, occurs throughout the lifespan and has been shown to play a role in learning, memory and in mood regulation. In adulthood it is influenced by extrinsic environmental factors such as exercise and stress. Intrinsic factors that regulate hippocampal neurogenesis include the orphan nuclear receptor TLX (Nr2e1) which is primarily expressed in the neurogenic niches of the brain. While mechanisms regulating adult hippocampal neurogenesis have been widely studied, less is known on how hippocampal neurogenesis is affected during adolescence. The aim of this study was to investigate the influence of both TLX and isolation stress on exercise-induced increases in neurogenesis in running and sedentary conditions during adolescence. Single- (isolation stress) wild type and Nr2e1-/- mice or pair-housed wild type mice were housed in sedentary conditions or allowed free access to running wheels for 3 wk during adolescence. A redn. of neuronal survival was evident in mice lacking TLX, and exercise did not increase hippocampal neurogenesis in these Nr2e1-/- mice. This suggests that TLX is necessary for the pro-neurogenic effects of exercise during adolescence. Interestingly, although social isolation during adolescence did not affect hippocampal neurogenesis, it prevented an exercise-induced increase in neurogenesis in the ventral hippocampus. Together these data demonstrate the importance of intrinsic and extrinsic factors in promoting an exercise-induced increase in neurogenesis at this key point in life.
- 308O’Leary, J. D.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. Regulation of Behaviour by the Nuclear Receptor TLX. Genes, Brain Behav. 2018, 17 (3), e12357, DOI: 10.1111/gbb.12357
- 309Kumar, R. A.; McGhee, K. A.; Leach, S.; Bonaguro, R.; Maclean, A.; Aguirre-Hernandez, R.; Abrahams, B. S.; Coccaro, E. F.; Hodgins, S.; Turecki, G.; Condon, A.; Muir, W. J.; Brooks-Wilson, A. R.; Blackwood, D. H.; Simpson, E. M. Initial Association of NR2E1 with Bipolar Disorder and Identification of Candidate Mutations in Bipolar Disorder, Schizophrenia, and Aggression through Resequencing. Am. J. Med. Genet., Part B 2008, 147B (6), 880– 889, DOI: 10.1002/ajmg.b.30696[Crossref], [PubMed], [CAS], Google Scholar313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFOnu7rJ&md5=4492c71454d36d17a372109768f8aeeeInitial association of NR2E1 with bipolar disorder and identification of candidate mutations in bipolar disorder, schizophrenia, and aggression through resequencingKumar, Ravinesh A.; McGhee, Kevin A.; Leach, Stephen; Bonaguro, Russell; Maclean, Alan; Aguirre-Hernandez, Rosalia; Abrahams, Brett S.; Coccaro, Emil F.; Hodgins, Sheilagh; Turecki, Gustavo; Condon, Anne; Muir, Walter J.; Brooks-Wilson, Angela R.; Blackwood, Douglas H.; Simpson, Elizabeth M.American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics (2008), 147B (6), 880-889CODEN: AJMGC9; ISSN:1552-4841. (Wiley-Liss, Inc.)Nuclear receptor 2E1 gene (NR2E1) resides within a 6q21-22 locus for bipolar disorder and schizophrenia. Mice deleted for Nr2e1 show altered neurogenesis, cortical and limbic abnormalities, aggression, hyperexcitability, and cognitive impairment. NR2E1 is therefore a positional and functional candidate for involvement in mental illness. We performed assocn. analyses in 394 patients with bipolar disorder, 396 with schizophrenia, and 479 controls using six common markers and haplotypes. We also performed a comprehensive mutation screen of NR2E1, resequencing its entire coding region, complete 5' and 3' untranslated regions, consensus splice-sites, and evolutionarily conserved regions in 126 humans with bipolar disorder, schizophrenia, or aggressive disorders. NR2E1 was assocd. with bipolar disorder I and II [odds ratio (OR = 0.77, P = 0.013), bipolar disorder I (OR = 0.77, P = 0.015), bipolar disorder in females (OR = 0.72, P = 0.009), and with age at onset ≤25 years (OR = 0.67, P = 0.006)], all of which remained significant after correcting for multiple comparisons. We identified eight novel candidate mutations that were absent in 325 controls; four of these were predicted to alter known neural transcription factor binding sites. Analyses of NR2E1 mRNA in human brain revealed forebrain-specific transcription. The data presented support the hypothesis that genetic variation at NR2E1 may be assocd. with susceptibility to brain-behavior disorders.
- 310Wang, Y. Y.; Hsu, S. H.; Tsai, H. Y.; Cheng, M. C. Genetic Analysis of the NR2E1 Gene as a Candidate Gene of Schizophrenia. Psychiatry Res. 2020, 293, 113386, DOI: 10.1016/j.psychres.2020.113386[Crossref], [PubMed], [CAS], Google Scholar314https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1ejsrnF&md5=1e82a84d45a065258e03a4547d384900Genetic analysis of the NR2E1 gene as a candidate gene of schizophreniaWang, Yu-Yuan; Hsu, Shih-Hsin; Tsai, Hsin-Yao; Cheng, Min-ChihPsychiatry Research (2020), 293 (), 113386CODEN: PSRSDR; ISSN:0165-1781. (Elsevier Ltd.)NR2E1 is implicated in the regulation of neurogenesis and considered as a candidate gene for schizophrenia. We resequenced all the exons of NR2E1 in 547 patients with schizophrenia and 567 controls from Taiwan. We identified five common SNPs with no assocn. with patients with schizophrenia. Further haplotype-based assocn. anal. showed that two haplotypes within NR2E1 were correlated with the schizophrenia risk. Four rare mutations located at untranslated regions were identified in patients with schizophrenia but not in our control sample. The present study suggests that NR2E1 is likely to play a significant role in conferring susceptibility to schizophrenia.
- 311Liu, H. K.; Wang, Y.; Belz, T.; Bock, D.; Takacs, A.; Radlwimmer, B.; Barbus, S.; Reifenberger, G.; Lichter, P.; Schütz, G. The Nuclear Receptor Tailless Induces Long-Term Neural Stem Cell Expansion and Brain Tumor Initiation. Genes Dev. 2010, 24 (7), 683– 695, DOI: 10.1101/gad.560310[Crossref], [PubMed], [CAS], Google Scholar315https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltFWlsrc%253D&md5=21efa027164c31a2ca1f7c76df1c8436The nuclear receptor tailless induces long-term neural stem cell expansion and brain tumor initiationLiu, Hai-Kun; Wang, Ying; Belz, Thorsten; Bock, Dagmar; Takacs, Andrea; Radlwimmer, Bernhard; Barbus, Sebastian; Reifenberger, Guido; Lichter, Peter; Schuetz, GuentherGenes & Development (2010), 24 (7), 683-695CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)Malignant gliomas are the most common primary brain tumors, and are assocd. with frequent resistance to therapy as well as poor prognosis. Here we demonstrate that the nuclear receptor tailless (Tlx), which in the adult is expressed exclusively in astrocyte-like B cells of the subventricular zone, acts as a key regulator of neural stem cell (NSC) expansion and brain tumor initiation from NSCs. Overexpression of Tlx antagonizes age-dependent exhaustion of NSCs in mice and leads to migration of stem/progenitor cells from their natural niche. The increase of NSCs persists with age, and leads to efficient prodn. of newborn neurons in aged brain tissues. These cells initiate the development of glioma-like lesions and gliomas. Glioma development is accelerated upon loss of the tumor suppressor p53. Tlx-induced NSC expansion and gliomagenesis are assocd. with increased angiogenesis, which allows for the migration and maintenance of brain tumor stem cells in the perivascular niche. We also demonstrate that Tlx transcripts are overexpressed in human primary glioblastomas in which Tlx expression is restricted to a subpopulation of nestin-pos. perivascular tumor cells. Our study clearly demonstrates how NSCs contribute to brain tumorigenesis driven by a stem cell-specific transcription factor, thus providing novel insights into the histogenesis and mol. pathogenesis of primary brain tumors.
- 312Park, H.-J.; Kim, J.-K.; Jeon, H.-M.; Oh, S.-Y.; Kim, S.-H.; Park, M.-J.; Soeda, A.; Nam, D.-H.; Kim, H. The Neural Stem Cell Fate Determinant TLX Promotes Tumorigenesis and Genesis of Cells Resembling Glioma Stem Cells. Mol. Cells 2010, 30 (5), 403– 408, DOI: 10.1007/s10059-010-0122-z[Crossref], [PubMed], [CAS], Google Scholar316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVyhur7L&md5=fa4f8b28fd33d8e372d1364a2708d9b4The neural stem cell fate determinant TLX promotes tumorigenesis and genesis of cells resembling glioma stem cellsPark, Hyo-Jung; Kim, Jun-Kyum; Jeon, Hye-Min; Oh, Se-Yeong; Kim, Sung-Hak; Park, Myung-Jin; Soeda, Akio; Nam, Do-Hyun; Kim, HyunggeeMolecules and Cells (2010), 30 (5), 403-408CODEN: MOCEEK; ISSN:1016-8478. (Korean Society for Molecular and Cellular Biology)A growing body of evidence indicates that deregulation of stem cell fate determinants is a hallmark of many types of malignancies. The neural stem cell fate determinant TLX plays a pivotal role in neurogenesis in the adult brain by maintaining neural stem cells. Here, we report a tumorigenic role of TLX in brain tumor initiation and progression. Increased TLX expression was obsd. in a no. of glioma cells and glioma stem cells, and correlated with poor survival of patients with gliomas. Ectopic expression of TLX in the U87MG glioma cell line and Ink4a/Arf-deficient mouse astrocytes (Ink4a/Arf-/- astrocytes) induced cell proliferation with a concomitant increase in cyclin D expression, and accelerated foci formation in soft agar and tumor formation in in vivo transplantation assays. Furthermore, overexpression of TLX in Ink4a/Arf-/- astrocytes inhibited cell migration and invasion and promoted neurosphere formation and Nestin expression, which are hallmark characteristics of glioma stem cells, under stem cell culture conditions. Our results indicate that TLX is involved in glioma stem cell genesis and represents a potential therapeutic target for this type of malignancy.
- 313Louis, D. N.; Ohgaki, H.; Wiestler, O. D.; Cavenee, W. K.; Burger, P. C.; Jouvet, A.; Scheithauer, B. W.; Kleihues, P. The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathologica 2007, 114, 97– 109[Crossref], [PubMed], [CAS], Google Scholar317https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2svgvVCltA%253D%253D&md5=41874b633369fa8ba13d31f1d2efc114The 2007 WHO classification of tumours of the central nervous systemLouis David N; Ohgaki Hiroko; Wiestler Otmar D; Cavenee Webster K; Burger Peter C; Jouvet Anne; Scheithauer Bernd W; Kleihues PaulActa neuropathologica (2007), 114 (2), 97-109 ISSN:0001-6322.The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO 'Blue Book', the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide.
- 314Cui, Q.; Yang, S.; Ye, P.; Tian, E.; Sun, G.; Zhou, J.; Sun, G.; Liu, X.; Chen, C.; Murai, K.; Zhao, C.; Azizian, K. T.; Yang, L.; Warden, C.; Wu, X.; D’Apuzzo, M.; Brown, C.; Badie, B.; Peng, L.; Riggs, A. D.; Rossi, J. J.; Shi, Y. Downregulation of TLX Induces TET3 Expression and Inhibits Glioblastoma Stem Cell Self-Renewal and Tumorigenesis. Nat. Commun. 2016, 7, 10637, DOI: 10.1038/ncomms10637[Crossref], [PubMed], [CAS], Google Scholar318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVOks7Y%253D&md5=78353fc29bb03ee6cb4329dca2ef64ddDownregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesisCui, Qi; Yang, Su; Ye, Peng; Tian, E.; Sun, Guoqiang; Zhou, Jiehua; Sun, Guihua; Liu, Xiaoxuan; Chen, Chao; Murai, Kiyohito; Zhao, Chunnian; Azizian, Krist T.; Yang, Lu; Warden, Charles; Wu, Xiwei; D'Apuzzo, Massimo; Brown, Christine; Badie, Behnam; Peng, Ling; Riggs, Arthur D.; Rossi, John J.; Shi, YanhongNature Communications (2016), 7 (), 10637CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)Glioblastomas have been proposed to be maintained by highly tumorigenic glioblastoma stem cells (GSCs) that are resistant to current therapy. Therefore, targeting GSCs is crit. for developing effective therapies for glioblastoma. In this study, we identify the regulatory cascade of the nuclear receptor TLX and the DNA hydroxylase Ten eleven translocation 3 (TET3) as a target for human GSCs. We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice. Treatment of human GSC-grafted mice with viral vector-delivered TLX shRNA or nanovector-delivered TLX siRNA inhibits tumor development and prolongs survival. Moreover, we identify TET3 as a potent tumor suppressor downstream of TLX to regulate the growth and self-renewal in GSCs. This study identifies the TLX-TET3 axis as a potential therapeutic target for glioblastoma.
- 315Dueva, E.; Singh, K.; Kalyta, A.; LeBlanc, E.; Rennie, P. S.; Cherkasov, A. Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor. Molecules 2018, 23 (11), 2967, DOI: 10.3390/molecules23112967[Crossref], [CAS], Google Scholar319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmt1Gis78%253D&md5=e826cc00b8f2c6a06cc64b7d1aa126cbComputer-aided discovery of small molecule inhibitors of transcriptional activity of TLX (NR2E1) nuclear receptorDueva, Evgenia; Singh, Kriti; Kalyta, Anastasia; LeBlanc, Eric; Rennie, Paul S.; Cherkasov, ArtemMolecules (2018), 23 (11), 2967/1-2967/10CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Orphan nuclear receptor TLX (NR2E1) plays a crit. role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in prostate and breast cancer. Therefore, inhibitors of TLX transcriptional activity may have a significant impact on the treatment of several crit. malignancies. However, the TLX protein possesses a non-canonical ligand-binding domain (LBD), which lacks a ligand-binding pocket (conventionally targeted in case of nuclear receptors) that complicates the development of small mol. inhibitors of TLX. Herein, we utilized a rational structure-based design approach to identify small mols. targeting the Atro-box binding site of human TLX LBD. As a result of virtual screening of 7 million mol. structures, 97 compds. were identified and evaluated in the TLX-responsive luciferase reporter assay. Among those, three chems. demonstrated 40-50% inhibition of luciferase-detected transcriptional activity of the TLX orphan nuclear receptor at a dose of 35 μM. The identified compds. represent the first class of small mol. inhibitors of TLX transcriptional activity identified via methods of computer-aided drug discovery.
- 316Milbrandt, J. Nerve Growth Factor Induces a Gene Homologous to the Glucocorticoid Receptor Gene. Neuron 1988, 1 (3), 183– 188, DOI: 10.1016/0896-6273(88)90138-9[Crossref], [PubMed], [CAS], Google Scholar320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXmtVGgurw%253D&md5=51f5ce2172370c86806cd5dc1776be74Nerve growth factor induces a gene homologous to the glucocorticoid receptor geneMilbrandt, JeffreyNeuron (1988), 1 (3), 183-8CODEN: NERNET; ISSN:0896-6273.Nerve growth factor (NGF) is required for the development and survival of sympathetic and neural crest-derived sensory neurons. The mechanism of action of NGF has been extensively studied in the NGF-responsive rat pheochromocytoma cell line, PC12. When treated with NGF, PC12 cells initiate neurite outgrowth and differentiate into cells with a neuronal phenotype. This process is prevented by RNA synthesis inhibitors. NGFI-B Is a gene, identified by differential hybridization, that is rapidly, but transiently induced in PC12 cells by NGF. The nucleotide sequence of the NGFI-B gene was detd., and it encodes a 61-kd protein with strong homologies to members of the glucocorticoid receptor gene family. The 2 regions of homol. between NGFI-B and this family of ligand-dependent transcriptional activators are the region corresponding th the DNA-binding domain and the region comprising the ligand-binding domain near the C-terminus. NGFI-B, as a possible ligand-dependent transcriptional activator induced by NGF, may play a role in initiating NGF-induced differentiation.
- 317Wang, Z.; Benoit, G.; Liu, J.; Prasad, S.; Aarnisalo, P.; Liu, X.; Xu, H.; Walker, N. P. C.; Perlmann, T. Structure and Function of Nurr1 Identifies a Class of Ligand- Independent Nuclear Receptors. Nature 2003, 423 (6939), 555– 560, DOI: 10.1038/nature01645[Crossref], [PubMed], [CAS], Google Scholar321https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktVygtb4%253D&md5=d19448447ffb618404ae84e4aa37c505Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptorsWang, Zhulun; Benoit, Gerard; Liu, Jinsong; Prasad, Srividya; Aarnisalo, Piia; Liu, Xiaohong; Xu, Haoda; Walker, Nigel P. C.; Perlmann, ThomasNature (London, United Kingdom) (2003), 423 (6939), 555-560CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Members of the nuclear receptor (NR) superfamily of transcription factors modulate gene transcription in response to small lipophilic mols. Transcriptional activity is regulated by ligands binding to the carboxy-terminal ligand-binding domains (LBDs) of cognate NRs. A subgroup of NRs referred to as 'orphan receptors' lack identified ligands, however, raising issues about the function of their LBDs. Here we report the crystal structure of the LBD of the orphan receptor Nurr1 at 2.2 Å resoln. The Nurr1 LBD adopts a canonical protein fold resembling that of agonist-bound, transcriptionally active LBDs in NRs, but the structure has two distinctive features. First, the Nurr1 LBD contains no cavity as a result of the tight packing of side chains from several bulky hydrophobic residues in the region normally occupied by ligands. Second, Nurr1 lacks a 'classical' binding site for coactivators. Despite these differences, the Nurr1 LBD can be regulated in mammalian cells. Notably, transcriptional activity is correlated with the Nurr1 LBD adopting a more stable conformation. Our findings highlight a unique structural class of NRs and define a model for ligand-independent NR function.
- 318Murphy, E. P.; Conneely, O. M. Neuroendocrine Regulation of the Hypothalamic Pituitary Adrenal Axis by the Nurr1/Nur77 Subfamily of Nuclear Receptors. Mol. Endocrinol. 1997, 11 (1), 39– 47, DOI: 10.1210/mend.11.1.9874[Crossref], [PubMed], [CAS], Google Scholar322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXhvFKitg%253D%253D&md5=79bd59c463059604b5934fadd9dc5a1aNeuroendocrine regulation of the hypothalamic pituitary adrenal axis by the nurr1/nur77 subfamily of nuclear receptorsMurphy, Evelyn P.; Conneely, Orla M.Molecular Endocrinology (1997), 11 (1), 39-47CODEN: MOENEN; ISSN:0888-8809. (Endocrine Society)The present study was designed to examine the role of nurr1/nur77 subfamily of nuclear receptor transcription factors in the regulation of the hypothalamic/pituitary/adrenal axis at the neuroendocrine level. The authors demonstrate that this nuclear receptor subfamily can regulate the expression of the CRF and POMC genes by interacting with a specific cis-acting sequence in their proximal promoter regions. To examine the physiol. significance of this response, the authors have focused on the POMC gene. The authors provide evidence that nurr1 and nur77 are rapidly induced by CRF in primary pituitary cells and that this induction is mimicked by forskolin in an anterior cell line. Further, the authors demonstrate that both nurr1- and forskolin-dependent induction of a POMC-chloramphenicol acetyltransferase reporter gene are inhibited by mutation of the nurr1-binding site within the POMC promoters and that this site alone can confer cAMP responsiveness to a heterologous promoter. Finally, the authors provide evidence that the nurr1/nur77 response sequences pivotal to both nurr1/nur77-dependent pos. regulation and glucocorticoid receptor-dependent neg. regulation of the POMC gene. These data strongly support the conclusion that the nurr1/nur77 subfamily plays an important coordinate neuroendocrine-regulatory role at all levels of the hypothalamic/pituitary/adrenal axis.
- 319Paulsen, R. E.; Granås, K.; Johnsen, H.; Rolseth, V.; Sterri, S. Three Related Brain Nuclear Receptors, NGFI-B, Nurr1, and NOR-1, as Transcriptional Activators. J. Mol. Neurosci. 1995, 6 (4), 249– 255, DOI: 10.1007/BF02736784[Crossref], [PubMed], [CAS], Google Scholar323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XivV2rtLY%253D&md5=d9a21c3adc12d98742ca4ca27993f1c6Three related brain nuclear receptors, NGFI-B, Nurr1, and NOR-1, as transcriptional activatorsPaulsen, Ragnhild E.; Granas, Kjersti; Johnsen, Helge; Rolseth, Veslemoy; Sterri, SigrunJournal of Molecular Neuroscience (1995), 6 (4), 249-255CODEN: JMNEES; ISSN:0895-8696. (Humana)Three related orphan nuclear receptors that are expressed in the brain, NGFI-B, Nurr1, and NOR-1, were studied to compare their function as transcriptional activators. NGFI-B was able to activate (in the absence of added hormone) in CV1 cells both an NGFI-B-responsive luciferase reporter gene (contg. eight copies of a response element for NGFI-B upstream of a basal prolactin promoter driving the luciferase gene, NBRE8-LUC), a similar thyroid hormone-receptor-responsive reporter gene (TRE3-LUC), and a reporter gene with an authentic promoter from a Xenopus vitellogenin gene contg. two binding sites for the estrogen receptor (vit-LUC). NGFI-B activated NBRE8-LUC and TRE3-LUC (but not the vit-LUC) with an amino-terminal activation domain. Nurr1 was less promiscuous as a transcriptional activator, activating the NBRE8-LUC better than NGFI-B, but less than NGFI-B at the other reporter genes. NOR-1 activated only the NBRE8-LUC reporter gene. These results indicate that closely related nuclear receptors may differentiate between response elements or promoters and that difficult activation mechanisms exist depending on the promoter. This may contribute to regulation of specificity of target gene expression in the brain.
- 320Maira, M.; Martens, C.; Philips, A.; Drouin, J. Heterodimerization between Members of the Nur Subfamily of Orphan Nuclear Receptors as a Novel Mechanism for Gene Activation. Mol. Cell. Biol. 1999, 19 (11), 7549– 7557, DOI: 10.1128/MCB.19.11.7549[Crossref], [PubMed], [CAS], Google Scholar324https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmvFekt7k%253D&md5=6216924bd742d76309b033c091d273fdHeterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activationMaira, Mario; Martens, Christine; Philips, Alexandre; Drouin, JacquesMolecular and Cellular Biology (1999), 19 (11), 7549-7557CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)The authors have recently shown that the orphan nuclear receptor Nur77 (NGFI-B) is most active in transcription when it is interacting with a cognate DNA sequence as a homodimer. Further, the authors have shown that the target for Nur77 dimers, the Nur response element (NurRE), is responsive to physiol. stimuli in both endocrine and lymphoid cells, whereas other DNA targets of Nur77 action are not. The Nur77 subfamily also includes two related receptors, Nur-related factor 1 (Nurr1) and neuron-derived orphan receptor 1 (NOR-1). Often, more than one member of this subfamily is induced in response to extracellular signals. The authors now show that Nur77 and Nurr1 form heterodimers in vitro in the presence or absence of NurRE, and the authors have documented interactions between these proteins in vivo by using a two-hybrid system in mammalian cells. These heterodimers synergistically enhance transcription from NurRE reporters in comparison to that seen with homodimers. The naturally occurring NurRE from the pro-opiomelanocortin gene preferentially binds and activates transcription in the presence of Nur77 homo- or heterodimers, while a consensus NurRE sequence does not show this preference. Taken together, the data indicate that members of the Nur77 subfamily are most potent as heterodimers and that different dimers exhibit target sequence preference. Thus, the authors propose that a combinatorial code relying on specific NurRE sequences might be responsible for the activation of subsets of target genes by one of the members of the Nur77 subfamily of transcription factors.
- 321Perlmann, T.; Jansson, L. A Novel Pathway for Vitamin A Signaling Mediated by RXR Heterodimerization with NGFI-B and NURR1. Genes Dev. 1995, 9 (7), 769– 782, DOI: 10.1101/gad.9.7.769[Crossref], [PubMed], [CAS], Google Scholar325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXltVaht7c%253D&md5=c9ea7577edf4a5b92721144a5ef1382fA novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1Perlmann, Thomas; Jansson, LottieGenes & Development (1995), 9 (7), 769-82CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)In addn. to its role as a 9-cis retinoic acid receptor, RXR has an important role in the regulation of multiple hormonal pathways through heterodimerization with nuclear receptors. Here, we show that two orphan receptors, NGFI-B and NURR1, which have been shown previously to interact with DNA as monomers, also can heterodimerize with RXR. These heterodimers bind selectively to a class of retinoic acid response elements composed of direct repeats spaced by 5 nucleotides. In this respect they are similar to heterodimers formed between RXR and the receptor for all-trans retinoic acid, RAR. However, whereas RXR is inhibited in the RXR-RAR heterodimer, NGFI-B/NURR1 promote efficient activation in response to RXR ligands and therefore shift RXR from a silent to an active heterodimerization partner. These data show that NGFI-B and NURR1 can increase the potential of RXR to modulate gene expression in a ligand-dependent manner by allowing a distinct class of direct repeats to serve as specific RXR response elements. Because expression of both NGFI-B and NURR1 is rapidly induced by various growth factors, these findings also suggest a novel mechanism for convergence between vitamin A or retinoid and growth factor signaling pathways.
- 322Xiao, Q.; Castillo, S. O.; Nikodem, V. M. Distribution of Messenger RNAs for the Orphan Nuclear Receptors NURR1 and NUR77 (NGFI-B) in Adult Rat Brain Using in Situ Hybridization. Neuroscience 1996, 75 (1), 221– 230, DOI: 10.1016/0306-4522(96)00159-5[Crossref], [PubMed], [CAS], Google Scholar326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmslGhu7c%253D&md5=4a9fc77c30696c5fafd790f34ace88d4Distribution of messenger RNAs for the orphan nuclear receptors Nurr1 and Nur77 (NGFI-B) in adult rat brain using in situ hybridizationXiao, Q.; Castillo, S. O.; Nikodem, V. M.Neuroscience (Oxford) (1996), 75 (1), 221-230CODEN: NRSCDN; ISSN:0306-4522. (Elsevier)Nurr1 and Nur77 (NGFI-B) are orphan nuclear receptors, belonging to the steroid/thyroid hormone receptor gene superfamily. They have conserved amino acid sequence in the zinc-finger DNA binding domains and similar COOH-terminal regions, but have no known ligands. However, different expression patterns during brain development and tissue distributions of these mRNAs imply that they might reflect a different transcriptional role in the brain. In this study, the regional and cellular expression of mRNAs encoding these two proteins in rat brain has been detd. by in situ hybridization. Nurr1 mRNA is highly expressed in the piriform and entorhinal cortices, hippocampus, medial habenular and paraventricular thalamic nuclei. Moderate labeling was detected in layers II-V of most of the cerebral cortex, and in the dorsal lateral geniculate nucleus, substantia nigra (pars compacta and reticularis) and interpeduncular nucleus. No Nurr1 hybridization signal was seen in the rhombencephalon. In the cerebellum, Nurr1 mRNA is present in the internal granular cell layer and Purkinje cell layer. In contrast, Nur77 has a widespread distribution, with the highest level of expression in the cerebral cortex. Moderate hybridization signals were detected in the hippocampus, the lateral dorsal and posterior nuclei, reuniens thalamic nuclei, and paraventricular and supraoptic hypothalamic nuclei. In the rhombencephalon, higher signals were present in the medial and lateral vestibular, dorsal cochlear and facial, and raphe magnus nuclei. Nur77 signal was also detected in the nucleus of the spinal tract of the trigeminal nerve. In the cerebellum, Nur77 mRNA is highly expressed in the Purkinje cell layer and lateral deep nucleus of the cerebellum. Our results show that Nurr1 and Nur77 mRNAs have both overlapping and different distribution patterns within the brain, suggesting that they might regulate different sets of responsive genes.
- 323Zetterström, R. H.; Williams, R.; Perlmann, T.; Olson, L. Cellular Expression of the Immediate Early Transcription Factors Nurr1 and NGFI-B Suggests a Gene Regulatory Role in Several Brain Regions Including the Nigrostriatal Dopamine System. Mol. Brain Res. 1996, 41 (1–2), 111– 120, DOI: 10.1016/0169-328X(96)00074-5[Crossref], [PubMed], [CAS], Google Scholar327https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s%252FjvVentQ%253D%253D&md5=ae85e40af8cba5f2a83e641a50571d21Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine systemZetterstrom R H; Williams R; Perlmann T; Olson LBrain research. Molecular brain research (1996), 41 (1-2), 111-20 ISSN:0169-328X.Nurr1 and NGFI-B are closely related orphan members of the steroid-thyroid hormone receptor family involved in immediate early responses to stimuli such as growth factors. In-situ hybridization in the developing and adult mouse and rat demonstrated Nurr1 mRNA in several regions during early central nervous system (CNS) development. Expression persisted through the pre- and postnatal periods and was also found in several areas in the adult CNS. Positive areas include the olfactory bulb, parts of the cortex, the hippocampal formation and substantia nigra where Nurr1 and tyrosine hydroxylase mRNAs were co-expressed. 6-Hydroxydopamine-induced degeneration of mesencephalic dopamine neurons led to a corresponding loss of Nurr1 mRNA, demonstrating a link between Nurr1 and dopaminergic neurons. NGFI-B mRNA was not found in the prenatal CNS but was highly expressed in the adult brain in many areas including the olfactory bulb, cortex, basal ganglia and hippocampus. The spatiotemporal distribution of Nurr1 and NGFI-B mRNAs suggests that these transcription factors are involved in the development and maturation of specific sets of CNS neurons. The experimental data imply that one of these functions may be to control gene regulatory events important for development and function of those neurons that degenerate in patients with Parkinson's disease.
- 324Chao, L. C.; Wroblewski, K.; Zhang, Z.; Pei, L.; Vergnes, L.; Ilkayeva, O. R.; Ding, S. Y.; Reue, K.; Watt, M. J.; Newgard, C. B.; Pilch, P. F.; Hevener, A. L.; Tontonoz, P. Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77. Diabetes 2009, 58 (12), 2788– 2796, DOI: 10.2337/db09-0763[Crossref], [PubMed], [CAS], Google Scholar328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFKlurfN&md5=5c4064106cef9dec4dececf60f992564Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77Chao, Lily C.; Wroblewski, Kevin; Zhang, Zidong; Pei, Liming; Vergnes, Laurent; Ilkayeva, Olga R.; Ding, Shi Ying; Reue, Karen; Watt, Matthew J.; Newgard, Christopher B.; Pilch, Paul F.; Hevener, Andrea L.; Tontonoz, PeterDiabetes (2009), 58 (12), 2788-2796CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)Nur77 is an orphan nuclear receptor with pleotropic functions. Previous studies have identified Nur77 as a transcriptional regulator of glucose utilization genes in skeletal muscle and gluconeogenesis in liver. However, the net functional impact of these pathways is unknown. To examine the consequence of Nur77 signaling for glucose metab. in vivo, we challenged Nur77 null mice with high-fat feeding. Wild-type and Nur77 null mice were fed a high-fat diet (60% calories from fat) for 3 mo. We detd. glucose tolerance, tissue-specific insulin sensitivity, oxygen consumption, muscle and liver lipid content, muscle insulin signaling, and expression of glucose and lipid metab. genes. Mice with genetic deletion of Nur77 exhibited increased susceptibility to diet-induced obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp studies revealed greater high-fat diet-induced insulin resistance in both skeletal muscle and liver of Nur77 null mice compared with controls. Loss of Nur77 expression in skeletal muscle impaired insulin signaling and markedly reduced GLUT4 protein expression. Muscles lacking Nur77 also exhibited increased triglyceride content and accumulation of multiple even-chained acylcarnitine species. In the liver, Nur77 deletion led to hepatic steatosis and enhanced expression of lipogenic genes, likely reflecting the lipogenic effect of hyperinsulinemia. Collectively, these data demonstrate that loss of Nur77 influences systemic glucose metab. and highlight the physiol. contribution of muscle Nur77 to this regulatory pathway.
- 325Zhan, Y.; Chen, Y.; Zhang, Q.; Zhuang, J.; Tian, M.; Chen, H.; Zhang, L.; Zhang, H.; He, J.; Wang, W.; Wu, R.; Wang, Y.; Shi, C.; Yang, K.; Li, A.; Xin, Y.; Li, T. Y.; Yang, J. Y.; Zheng, Z.; Yu, C.; Lin, S.-C.; Chang, C.; Huang, P.; Lin, T.; Wu, Q. The Orphan Nuclear Receptor Nur77 Regulates LKB1 Localization and Activates AMPK. Nat. Chem. Biol. 2012, 8 (11), 897– 904, DOI: 10.1038/nchembio.1069[Crossref], [PubMed], [CAS], Google Scholar329https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlCqu7jF&md5=f00c49daf55792014107d6857e8b729bThe orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPKZhan, Yan-yan; Chen, Yan; Zhang, Qian; Zhuang, Jia-jia; Tian, Min; Chen, Hang-zi; Zhang, Lian-ru; Zhang, Hong-kui; He, Jian-ping; Wang, Wei-jia; Wu, Rong; Wang, Yuan; Shi, Chunfang; Yang, Kai; Li, An-zhong; Xin, Yong-zhen; Li, Terytty Yang; Yang, James Y.; Zheng, Zhong-hui; Yu, Chun-dong; Lin, Sheng-Cai; Chang, Chawn-shang; Huang, Pei-qiang; Lin, Tianwei; Wu, QiaoNature Chemical Biology (2012), 8 (11), 897-904CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Liver kinase B1 (LKB1) has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). The regulation of LKB1 function, however, is still poorly understood. Here we demonstrate that the orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. This Nur77 function is antagonized by the chem. compd. Et 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), which interacts with Nur77 with high affinity and at specific sites. TMPA binding of Nur77 results in the release and shuttling of LKB1 to the cytoplasm to phosphorylate AMPKα. Moreover, TMPA effectively reduces blood glucose and alleviates insulin resistance in type II db/db and high-fat diet- and streptozotocin-induced diabetic mice but not in diabetic littermates with the Nur77 gene knocked out. This study attains a mechanistic understanding of the regulation of LKB1-AMPK axis and implicates Nur77 as a new and amenable target for the design and development of therapeutics to treat metabolic diseases.
- 326Kurakula, K.; Vos, M.; Logiantara, A.; Roelofs, J. J.; Nieuwenhuis, M. A.; Koppelman, G. H.; Postma, D. S.; van Rijt, L. S.; de Vries, C. J. M. Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-KB Activity in Lung Epithelial Cells. J. Immunol. 2015, 195 (4), 1388– 1398, DOI: 10.4049/jimmunol.1401714[Crossref], [PubMed], [CAS], Google Scholar330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht12gtrbF&md5=1925aa0e74194a59c7e9d56ae504570aNuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial CellsKurakula, Kondababu; Vos, Mariska; Logiantara, Adrian; Roelofs, Joris J.; Nieuwenhuis, Maartje A.; Koppelman, Gerard H.; Postma, Dirkje S.; van Rijt, Leonie S.; de Vries, Carlie J. M.Journal of Immunology (2015), 195 (4), 1388-1398CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)Allergic asthma is characterized by persistent chronic airway inflammation, which leads to mucus hypersecretion and airway hyperresponsiveness. Nuclear receptor Nur77 plays a pivotal role in distinct immune and inflammatory cells and is expressed in eosinophils and lung epithelium. However, the role of Nur77 in allergic airway inflammation has not been studied so far. In the present study, we detd. the role of Nur77 in airway inflammation using a murine model of OVA-induced allergic airway inflammation. We found that OVA-challenged Nur77 knockout (KO) mice show significantly enhanced infiltration of inflammatory cells, including eosinophils and lymphocytes, and aggravated mucus prodn. The infiltration of macrophages is limited in this model and was similar in wild-type and Nur77 KO mice. Higher levels of Th2 cytokines were found in bronchoalveolar lavage fluid and draining lymph node cells of Nur77-KO mice, as well as increased serum IgG1 and IgG2a levels. Knockdown of Nur77 in human lung epithelial cells resulted in a marked increase in IκBα phosphorylation, corresponding with elevated NF-κB activity, whereas Nur77 overexpression decreased NF-κB activity. Consistently, Nur77 significantly decreased mRNA levels of inflammatory cytokines and Muc5ac expression and also attenuated mucus prodn. in lung epithelial cells. To further corroborate these findings, we searched for assocn. of single nucleotide polymorphisms in Nur77 gene with asthma and with the severity of bronchial hyperresponsiveness. We identified three Nur77 single nucleotide polymorphisms showing assocn. with severity of bronchial hyperresponsiveness in asthma patients. Collectively, these findings support a protective role of Nur77 in OVA-induced airway inflammation and identify Nur77 as a novel therapeutic target for airway inflammation.
- 327Hamers, A. A.J.; Vos, M.; Rassam, F.; Marinkovic, G.; Kurakula, K.; van Gorp, P. J.; de Winther, M. P.J.; Gijbels, M. J.J.; de Waard, V.; de Vries, C. J.M. Bone Marrow-Specific Deficiency of Nuclear Receptor Nur77 Enhances Atherosclerosis. Circ. Res. 2012, 110 (3), 428– 438, DOI: 10.1161/CIRCRESAHA.111.260760[Crossref], [PubMed], [CAS], Google Scholar331https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVert7g%253D&md5=6a1e5a07fb7e20e16114e45977399821Bone Marrow-Specific Deficiency of Nuclear Receptor Nur77 Enhances AtherosclerosisHamers, Anouk A. J.; Vos, Mariska; Rassam, Fadi; Marinkovic, Goran; Kurakula, Kondababu; van Gorp, Patrick J.; de Winther, Menno P. J.; Gijbels, Marion J. J.; de Waard, Vivian; de Vries, Carlie J. M.Circulation Research (2012), 110 (3), 428-438CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Rationale: Nuclear receptor Nur77, also known as NR4A1, TR3, or NGFI-B, is expressed in human atherosclerotic lesions in macrophages, endothelial cells, T cells and smooth muscle cells. Macrophages play a crit. role in atherosclerosis and the function of Nur77 in lesion macrophages has not yet been investigated. Objective: This study aims to delineate the function of Nur77 in macrophages and to assess the effect of bone marrow-specific deficiency of Nur77 on atherosclerosis. Methods and results: We investigated Nur77 in macrophage polarization using bone marrow-derived macrophages (BMM) from wild-type and Nur77-knockout (Nur77) mice. Nur77 BMM exhibit changed expression of M2-specific markers and an inflammatory M1-phenotype with enhanced expression of interleukin-12, IFNγ, and SDF-1α and increased NO synthesis in (non)-stimulated Nur77 BMM cells. SDF-1α expression in nonstimulated Nur77 BMM is repressed by Nur77 and the chemoattractive activity of Nur77 BMM is abolished by SDF-1α inhibiting antibodies. Furthermore, Nur77 mice show enhanced thioglycollate-elicited migration of macrophages and B cells. The effect of bone marrow-specific deficiency of Nur77 on atherosclerosis was studied in low d. lipoprotein receptor-deficient (Ldlr) mice. Ldlr mice with a Nur77-deficient bone marrow transplant developed 2.1-fold larger atherosclerotic lesions than wild-type bone marrow-transplanted mice. These lesions contain more macrophages, T cells, smooth muscle cells and larger necrotic cores. SDF-1α expression is higher in lesions of Nur77-transplanted mice, which may explain the obsd. aggravation of lesion formation. Conclusions: In conclusion, in bone marrow-derived cells the nuclear receptor Nur77 has an anti-inflammatory function, represses SDF-1α expression and inhibits atherosclerosis.
- 328Hanna, R. N.; Shaked, I.; Hubbeling, H. G.; Punt, J. A.; Wu, R.; Herrley, E.; Zaugg, C.; Pei, H.; Geissmann, F.; Ley, K.; Hedrick, C. C. NR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases Atherosclerosis. Circ. Res. 2012, 110 (3), 416– 427, DOI: 10.1161/CIRCRESAHA.111.253377[Crossref], [PubMed], [CAS], Google Scholar332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVert7s%253D&md5=c686ef9d972070d869945ec15f3e5beeNR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases AtherosclerosisHanna, Richard N.; Shaked, Iftach; Hubbeling, Harper G.; Punt, Jennifer A.; Wu, Runpei; Herrley, Erica; Zaugg, Claudia; Pei, Hong; Geissmann, Frederic; Ley, Klaus; Hedrick, Catherine C.Circulation Research (2012), 110 (3), 416-427CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Rationale: NR4A1 (Nur77) is a nuclear receptor that is expressed in macrophages and within atherosclerotic lesions, yet its function in atherosclerosis is unknown. Objective: Nur77 regulates the development of monocytes, particularly patrolling Ly6C monocytes that may be involved in resoln. of inflammation. We sought to det. how absence of nuclear receptor subfamily 4, group A, member 1 (NR4A1) in hematopoietic cells affected atherosclerosis development. Methods and results: Nur77 chimeric mice on a Ldlr background showed a 3-fold increase in atherosclerosis development when fed a Western diet for 20 wk, despite having a drastic redn. in Ly6C patrolling monocytes. In a second model, mice deficient in both Nur77 and ApoE (ApoENur77) also showed increased atherosclerosis after 11 wk of Western diet. Atherosclerosis was assocd. with a significant change in macrophage polarization toward a proinflammatory phenotype, with high expression of tumor necrosis factor-α and nitric oxide and low expression of Arginase-I. Moreover, we found increased expression of toll-like receptor 4 mRNA and protein in Nur77 macrophages as well as increased phosphorylation of the p65 subunit of NFκB. Inhibition of NFκB activity blocked excess activation of Nur77 macrophages. Conclusions: We conclude that the absence of Nur77 in monocytes and macrophages results in enhanced toll-like receptor signaling and polarization of macrophages toward a proinflammatory M1 phenotype. Despite having fewer monocytes, Nur77 mice developed significant atherosclerosis when fed a Western diet. These studies indicate that Nur77 is a novel target for modulating the inflammatory phenotype of monocytes and macrophages and may be important for regulation of atherogenesis.
- 329De Silva, S.; Han, S.; Zhang, X.; Huston, D. P.; Winoto, A.; Zheng, B. Reduction of the Incidence and Severity of Collagen-Induced Arthritis by Constitutive Nur77 Expression in the T Cell Lineage. Arthritis Rheum. 2005, 52 (1), 333– 338, DOI: 10.1002/art.20736[Crossref], [PubMed], [CAS], Google Scholar333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1Kit7o%253D&md5=3185bbf074edd734633505b13561ea00Reduction of the incidence and severity of collagen-induced arthritis by constitutive Nur77 expression in the T cell lineagede Silva, Swanthri; Han, Shuhua; Zhang, Xuejun; Huston, David P.; Winoto, Astar; Zheng, BiaoArthritis & Rheumatism (2005), 52 (1), 333-338CODEN: ARHEAW; ISSN:0004-3591. (John Wiley & Sons, Inc.)Objective: To test the hypothesis that constitutive expression of Nur77 in the T cell lineage will suppress the development and pathogenesis of collagen-induced arthritis (CIA) and to understand the mechanisms by which Nur77 overexpression influences the arthritogenic response to type II collagen (CII). Methods: Nur77-transgenic end wild-type C57BL/6 mice were immunized with CII and were monitored for the development and severity of arthritis. Pathol. changes were examd. by histol. and radiog. The effects of Nur77 overexpression on immune responses were evaluated by cytokine prodn. in vitro and serum levels of CII-specific antibodies. Sensitivity of T cells to apoptosis induction was analyzed in vitro following stimulation with anti-CD3 monoclonal antibody or glucocorticoid. Results: The incidence and severity of CIA was significantly decreased in Nur77-transgenic mice compared with wild-type controls. Attenuation of the disease was assocd. with increased apoptosis induction in transgenic T cells and decreased prodn. of CII-specific IgG2a antibodies in transgenic mice. Overexpression of Nur77 in the T cell compartment did not affect Th1/Th2 cytokine prodn. or balance. Conclusion: Nur77 overexpression in the T cell lineage attenuates the development and progression of CIA, probably by promoting activation-induced T cell apoptosis and by inhibiting CII-specific antibody prodn.
- 330Li, L.; Liu, Y.; Chen, H.; Li, F.; Wu, J.; Zhang, H.; He, J.; Xing, Y.; Chen, Y.; Wang, W.; Tian, X.; Li, A.; Zhang, Q.; Huang, P.; Han, J.; Lin, T.; Wu, Q. Impeding the Interaction between Nur77 and P38 Reduces LPS-Induced Inflammation. Nat. Chem. Biol. 2015, 11 (5), 339– 346, DOI: 10.1038/nchembio.1788[Crossref], [PubMed], [CAS], Google Scholar334https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlsVOns74%253D&md5=648de4a3c58bba85279ae13a37a6c0a2Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammationLi, Li; Liu, Yuan; Chen, Hang-zi; Li, Feng-wei; Wu, Jian-feng; Zhang, Hong-kui; He, Jian-ping; Xing, Yong-zhen; Chen, Yan; Wang, Wei-jia; Tian, Xu-yang; Li, An-zhong; Zhang, Qian; Huang, Pei-qiang; Han, Jiahuai; Lin, Tianwei; Wu, QiaoNature Chemical Biology (2015), 11 (5), 339-346CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine prodn. Nur77 directly assocs. with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compd., n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate (PDNPA), screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study assocs. the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.
- 331Beard, J. A.; Tenga, A.; Chen, T. The Interplay of NR4A Receptors and the Oncogene-Tumor Suppressor Networks in Cancer. Cell. Signalling 2015, 27 (2), 257– 266, DOI: 10.1016/j.cellsig.2014.11.009[Crossref], [PubMed], [CAS], Google Scholar335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2gsrfP&md5=06396e4f736fb8990292219337bb150cThe interplay of NR4A receptors and the oncogene-tumor suppressor networks in cancerBeard, Jordan A.; Tenga, Alexa; Chen, TaoshengCellular Signalling (2015), 27 (2), 257-266CODEN: CESIEY; ISSN:0898-6568. (Elsevier)A review. Nuclear receptor (NR) subfamily 4 group A (NR4A) is a family of three highly homologous orphan nuclear receptors that have multiple physiol. and pathol. roles, including some in cancer. These NRs are reportedly dysregulated in multiple cancer types, with many studies demonstrating pro-oncogenic roles for NR4A1 (Nur77) and NR4A2 (Nurr1). Addnl., NR4A1 and NR4A3 (Nor-1) are described as tumor suppressors in leukemia. The dysregulation and functions of the NR4A members are due to many factors, including transcriptional regulation, protein-protein interactions, and post-translational modifications. These various levels of intracellular regulation result from the signaling cross-talk of the NR4A members with various signaling pathways, many of which are relevant to cancer and likely explain the family members' functions in oncogenesis and tumor suppression. In this review, we discuss the multiple functions of the NR4A receptors in cancer and summarize a growing body of scientific literature that describes the interconnectedness of the NR4A receptors with various oncogene and tumor suppressor pathways.
- 332Li, H.; Kolluri, S. K.; Gu, J.; Dawson, M. I.; Cao, X.; Hobbs, P. D.; Lin, B.; Chen, G.; Lu, J.; Lin, F.; Xie, Z.; Fontana, J. A.; Reed, J. C.; Zhang, X. Cytochrome c Release and Apoptosis Induced by Mitochondrial Targeting of Nuclear Orphan Receptor TR3. Science 2000, 289 (5482), 1159– 1164, DOI: 10.1126/science.289.5482.1159[Crossref], [PubMed], [CAS], Google Scholar336https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmt1Wju74%253D&md5=eff25fa9c3782edaf7f7a70f0d8d00d5Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3Li, Hui; Kolluri, Siva Kumar; Gu, Jian; Dawson, Marcia I.; Cao, Xihua; Hobbs, Peter D.; Lin, Bingzhen; Chen, Guo-Quen; Lu, Jiang-Song; Lin, Feng; Xie, Zhihua; Fontana, Joseph A.; Reed, John C.; Zhang, Xiao-KunScience (Washington, D. C.) (2000), 289 (5482), 1159-1164CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)TR3, an immediate-early response gene and an orphan member of the steroid-thyroid hormone-retinoid receptor superfamily of transcription factors, regulates apoptosis through an unknown mechanism. In response to apoptotic stimuli, TR3 translocates from the nucleus to mitochondria to induce cytochrome c release and apoptosis. Mitochondrial targeting of TR3, but not its DNA binding and transactivation, is essential for its proapoptotic effect. Our results reveal a mechanism by which a nuclear transcription factor translocates to mitochondria to initiate apoptosis.
- 333Cao, X.; Liu, W.; Lin, F.; Li, H.; Kolluri, S. K.; Lin, B.; Han, Y.; Dawson, M. I.; Zhang, X. Retinoid X Receptor Regulates Nur77/Thyroid Hormone Receptor 3-Dependent Apoptosis by Modulating Its Nuclear Export and Mitochondrial Targeting. Mol. Cell. Biol. 2004, 24 (22), 9705– 9725, DOI: 10.1128/MCB.24.22.9705-9725.2004[Crossref], [PubMed], [CAS], Google Scholar337https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpslOnt74%253D&md5=159df472771d127c65299229117878d3Retinoid X receptor regulates Nur77/thyroid hormone receptor 3-dependent apoptosis by modulating its nuclear export and mitochondrial targetingCao, Xihua; Liu, Wen; Lin, Feng; Li, Hui; Kolluri, Siva Kumar; Lin, Bingzhen; Han, Young-hoon; Dawson, Marcia I.; Zhang, Xiao-kunMolecular and Cellular Biology (2004), 24 (22), 9705-9725CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)Retinoid X receptor (RXR) plays a central role in the regulation of intracellular receptor signaling pathways by acting as a ubiquitous heterodimerization partner of many nuclear receptors, including the orphan receptor Nur77 (also known as thyroid hormone receptor 3 or NGFI-B), which translocates from the nucleus to mitochondria, where it interacts with Bcl-2 to induce apoptosis. Here, we report that RXRα is required for nuclear export and mitochondrial targeting of Nur77 through their unique heterodimerization that is mediated by dimerization interfaces located in their DNA-binding domain. The effects of RXRα are attributed to a putative nuclear export sequence (NES) present in its carboxyl-terminal region. RXRα ligands suppress NES activity by inducing RXRα homodimerization or altering RXRα/Nur77 heterodimerization. The RXRα NES is also silenced by RXRα heterodimerization with retinoic acid receptor or vitamin D receptor. Consistently, we were able to show that the mitochondrial targeting of the RXRα/Nur77 heterodimer and its induction of apoptosis are potently inhibited by RXR ligands. Together, our results reveal a novel nongenotropic function of RXRα and its involvement in the regulation of the Nur77-dependent apoptotic pathway.
- 334Gilbert, F.; Morissette, M.; St-Hilaire, M.; Paquet, B.; Rouillard, C.; Di Paolo, T.; Lévesque, D. Nur77 Gene Knockout Alters Dopamine Neuron Biochemical Activity and Dopamine Turnover. Biol. Psychiatry 2006, 60 (6), 538– 547, DOI: 10.1016/j.biopsych.2006.04.023[Crossref], [PubMed], [CAS], Google Scholar338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XpvFels7o%253D&md5=2245f46b35f73767ddbeef7532dccf24Nur77 gene knockout alters dopamine turnoverGilbert, Francois; Morissette, Marc; St-Hilaire, Michel; Paquet, Brigitte; Rouillard, Claude; Di Paolo, Therese; Levesque, DanielBiological Psychiatry (2006), 60 (6), 538-547CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Inc.)Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors closely assocd. with dopamine neurotransmission in the central nervous system. Nur77 expression is strongly modulated by antipsychotic and anti-parkinsonian drugs in dopaminoceptive brain areas. However, the role of Nur77 in dopamine neuron activity and turnover remains elusive. We compared various behavioral and biochem. parameters between Nur77 knockout -/- and wild-type +/+ mice in basal and haloperidol-challenged conditions. We report here that Nur77-deficient mice display enhanced spontaneous locomotor activity, greater sensitivity to a small dose of the dopamine D2 receptor agonist quinpirole acting mainly at autoreceptor sites, and higher levels of the dopamine metabolite DOPAC relative to wild-type mice. Dopamine turnover disturbances are also found after acute challenge with haloperidol, a dopamine D2 receptor antagonist. These alterations are assocd. with increased tyrosine hydroxylase expression and activity, and reduced catechol-O-methyltransferase expression. Taken together, these results are consistent with the involvement of Nur77 in dopamine neuron biochem. activity and dopamine turnover.
- 335Rouillard, C.; Baillargeon, J.; Paquet, B.; St-Hilaire, M.; Maheux, J.; Lévesque, C.; Darlix, N.; Majeur, S.; Lévesque, D. Genetic Disruption of the Nuclear Receptor Nur77 (Nr4a1) in Rat Reduces Dopamine Cell Loss and L-Dopa-Induced Dyskinesia in Experimental Parkinson’s Disease. Exp. Neurol. 2018, 304, 143– 153, DOI: 10.1016/j.expneurol.2018.03.008[Crossref], [PubMed], [CAS], Google Scholar339https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlslGqsr0%253D&md5=fb94f98547dcfa8522268881b7d64caaGenetic disruption of the nuclear receptor Nur77 (Nr4a1) in rat reduces dopamine cell loss and L-Dopa-induced dyskinesia in experimental Parkinson's diseaseRouillard, Claude; Baillargeon, Joanie; Paquet, Brigitte; St-Hilaire, Michel; Maheux, Jerome; Levesque, Catherine; Darlix, Noemie; Majeur, Simon; Levesque, DanielExperimental Neurology (2018), 304 (), 143-153CODEN: EXNEAC; ISSN:0014-4886. (Elsevier Inc.)Parkinson's disease (PD) is an idiopathic progressive neurodegenerative disorder characterized by the loss of midbrain dopamine neurons. Levodopa (L-dopa) is the main pharmacol. approach to relieve PD motor symptoms. However, chronic treatment with L-Dopa is inevitably assocd. with the generation of abnormal involuntary movements (L-Dopa-induced dyskinesia). We have previously shown that Nr4a1 (Nur77), a transcription factor of the nuclear receptor family, is closely assocd. with dopamine neurotransmission in the mature brain. However, the role of Nr4a1 in the etiol. of PD and its treatment remain elusive. We report here that the neurotoxin 6-hydroxydopamine in rat lead to a rapid up-regulation of Nr4a1 in the substantia nigra. Genetic disruption of Nr4a1 in rat reduced neurotoxin-induced dopamine cell loss and L-Dopa-induced dyskinesia, whereas virally-driven striatal overexpression of Nr4a1 enhanced or partially restored involuntary movements induced by chronic L-Dopa in wild type and Nr4a1-deficient rats, resp. Collectively, these results suggest that Nr4a1 is involved in dopamine cell loss and L-Dopa-induced dyskinesia in exptl. PD.
- 336Novak, G.; Gallo, A.; Zai, C. C.; Meltzer, H. Y.; Lieberman, J. A.; Potkin, S. G.; Voineskos, A. N.; Remington, G.; Kennedy, J. L.; Levesque, D.; Le Foll, B. Association of the Orphan Nuclear Receptor NR4A1 with Tardive Dyskinesia. Psychiatr. Genet. 2010, 20 (1), 39– 43, DOI: 10.1097/YPG.0b013e3283351221[Crossref], [PubMed], [CAS], Google Scholar340https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MfksFWqsw%253D%253D&md5=6e5f0d45e83d6687932ec5eac2b7948dAssociation of the orphan nuclear receptor NR4A1 with tardive dyskinesiaNovak Gabriela; Gallo Alexandra; Zai Clement C; Meltzer Herbert Y; Lieberman Jeffrey A; Potkin Steven G; Voineskos Aristotle N; Remington Gary; Kennedy James L; Levesque Daniel; Le Foll BernardPsychiatric genetics (2010), 20 (1), 39-43 ISSN:.Recent evidence has identified the NR4A1 (NUR77, NGFI-B) gene as a strong candidate for involvement in tardive dyskinesia (TD). We have investigated the association of six single nucleotide polymorphisms within the NR4A family of genes with TD in a sample of 171 patients with schizophrenia of Caucasian descent. The NR4A1 single nucleotide polymorphism (SNP) marker rs2603751 showed a nominal association with the risk of TD, as well as with the extent of TD based on the Abnormal Involuntary Movements Scale (AIMS) scores. The haplotype generated by the markers rs2603751 and rs2701124 also showed association with TD and, after adjustment for multiple testing, both the NR4A1 marker rs2603751 and the haplotype continued to show a trend toward association with TD. Although the results of this study are limited by a small sample size, it presents important pilot data and warrants further investigation of the involvement of NR4A1 variants in TD.
- 337St-Hilaire, M.; Bourhis, E.; Lévesque, D.; Rouillard, C. Impaired Behavioural and Molecular Adaptations to Dopamine Denervation and Repeated L-DOPA Treatment in Nur77-Knockout Mice. Eur. J. Neurosci. 2006, 24 (3), 795– 805, DOI: 10.1111/j.1460-9568.2006.04954.x[Crossref], [PubMed], [CAS], Google Scholar341https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28rgs1Ontg%253D%253D&md5=d8bc0c6c02ecf8417643e3d95b1c153bImpaired behavioural and molecular adaptations to dopamine denervation and repeated L-DOPA treatment in Nur77-knockout miceSt-Hilaire Michel; Bourhis Emmanuelle; Levesque Daniel; Rouillard ClaudeThe European journal of neuroscience (2006), 24 (3), 795-805 ISSN:0953-816X.We have previously shown that dopamine (DA) denervation and repeated L-DOPA treatment modulate the pattern of Nur77 mRNA expression in the striatum. However, the exact role of this nuclear receptor in L-DOPA-induced molecular and behavioural adaptations observed in animal models of Parkinson's disease is still unknown. In the present study, we investigated the effects of Nur77 gene deletion on the development of behavioural sensitization and on changes in the regulation of neuropeptides and DA D(3) receptor expression following DA denervation and repeated L-DOPA treatment in Nur77+/+ and Nur77-/- hemiparkinsonian mice. One week postsurgery, hemiparkinsonian mice were treated with L-DOPA (10 mg/kg) plus benserazide (3 mg/kg) once a day for 7 days. Despite similar extents of nigrostriatal denervation, L-DOPA-induced rotational response was exacerbated in Nur77-/- mice compared to Nur77+/+ ones. However, the rate of increase of the rotational behaviour after repeated L-DOPA injections was similar in the two mouse strains. Lesioning the nigrostriatal pathway increased enkephalin (ENK) and neurotensin (NT) mRNA levels in both mouse strains. However, the up-regulation of these neuropeptides was significantly reduced in Nur77-/- mice. There was no difference in the modulation of D3 receptor density and dynorphin (DYN) mRNA expression between the two mouse strains. The present results suggest that Nur77 is involved in setting the threshold level for L-DOPA-induced rotational behaviour, rather than controlling the development of behavioural sensitization. This specific behavioural change is associated with a selective regulation of neuropeptide expression specifically in the indirect striatal output pathway.
- 338Éthier, I.; Beaudry, G.; St-Hilaire, M.; Milbrandt, J.; Rouillard, C.; Lévesque, D. The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression. Neuropsychopharmacology 2004, 29 (2), 335– 346, DOI: 10.1038/sj.npp.1300318[Crossref], [PubMed], [CAS], Google Scholar342https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXksl2hsg%253D%253D&md5=1fdc8193085152f4c93f68c458f51006The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene ExpressionEthier, Isabelle; Beaudry, Genevieve; St-Hilaire, Michel; Milbrandt, Jeff; Rouillard, Claude; Levesque, DanielNeuropsychopharmacology (2004), 29 (2), 335-346CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)Despite extensive investigation, the cellular mechanisms responsible for neuroleptic actions remain elusive. The authors have previously shown that neuroleptics modulated the expression of some members of the ligand-activated transcription factors (nuclear receptors) including the nerve-growth factor inducible gene B (NGFI-B or Nur77) and retinoid X receptor (RXR) isoforms. Using genetic and pharmacol. approaches, the authors investigated the role of NGFI-B and retinoids in acute behavioral and biochem. responses to dopamine antagonists. NGFI-B knockout (KO) mice display a profound alteration of haloperidol-induced catalepsy and striatal neuropeptide gene expression. Haloperidol-induced increase of striatal enkephalin mRNA is totally abolished in NGFI-B KO mice whereas the increase of neurotensin mRNA expression is reduced by 50%. Interestingly, catalepsy induced by raclopride, a specific dopamine D2/D3 antagonist is completely abolished in NGFI-B-deficient mice whereas the cataleptic response to SCH 23390, a dopamine D1 agonist, is preserved. Accordingly, the effects of haloperidol on striatal c-fos, Nor-1, and dynorphin mRNA expression are also preserved in NGFI-B-deficient mice. The cataleptic response and the increase of enkephalin mRNA expression induced by haloperidol can also be suppressed by administration of retinoid ligands 9-cis retinoic acid and docosahexaenoic acid. In addn., the authors demonstrate that haloperidol enhances colocalization of NGFI-B and RXRγ1 isoform mRNAs, suggesting that both NGFI-B and a RXR isoform are highly coexpressed after haloperidol administration. The data demonstrate, for the first time, that NGFI-B and retinoids are actively involved in the mol. cascade induced by neuroleptic drugs.
- 339Mahmoudi, S.; Samadi, P.; Gilbert, F.; Ouattara, B.; Morissette, M.; Grégoire, L.; Rouillard, C.; Di Paolo, T.; Lévesque, D. Nur77 MRNA Levels and L-Dopa-Induced Dyskinesias in MPTP Monkeys Treated with Docosahexaenoic Acid. Neurobiol. Dis. 2009, 36 (1), 213– 222, DOI: 10.1016/j.nbd.2009.07.017[Crossref], [PubMed], [CAS], Google Scholar343https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFajtLvJ&md5=f5479f7d4c5660bf43525545402d7516Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acidMahmoudi, Souha; Samadi, Pershia; Gilbert, Francois; Ouattara, Bazoumana; Morissette, Marc; Gregoire, Laurent; Rouillard, Claude; Di Paolo, Therese; Levesque, DanielNeurobiology of Disease (2009), 36 (1), 213-222CODEN: NUDIEM; ISSN:0969-9961. (Elsevier B.V.)We have previously shown that docosahexaenoic acid (DHA) significantly reduced L-Dopa-induced dyskinesia (LID) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys. In the present study, we measured for the first time mRNA levels of Nur77, an orphan nuclear receptor that participates to adaptive and/or aberrant dopamine-related behaviors, and retinoid X receptor γ1 (RXRγ1), a putative brain receptor for DHA and transcriptional partner of Nur77, in MPTP monkeys treated with L-Dopa and DHA. The RXRγ1 mRNA is strongly expressed in monkey caudate nucleus and putamen, but no change in levels of RXRγ1 was obsd. following MPTP and L-Dopa treatments. On the other hand, denervation reduced Nur77 mRNA levels, whereas chronic L-Dopa treatment strongly induced Nur77 transcripts. These modulations are taking place in substance P pos. cells and are assocd. with both caudate-putamen matrix and striosome compartments. Interestingly, combination of L-Dopa with DHA further increases Nur77 mRNA levels in the anterior caudate-putamen, and mainly in striosomes. This is accompanied by a significant inverse correlation between Nur77 mRNA levels and dyskinetic scores. Taken together, our results show that Nur77 expression is modulated following dopamine denervation and chronic L-Dopa therapy in a non-human primate model of Parkinson's disease, and suggest that strong modulation of Nur77 expression might be linked to a reduced risk to develop LIDs.
- 340Mount, M. P.; Zhang, Y.; Amini, M.; Callaghan, S.; Kulczycki, J.; Mao, Z.; Slack, R. S.; Anisman, H.; Park, D. S. Perturbation of Transcription Factor Nur77 Expression Mediated by Myocyte Enhancer Factor 2D (MEF2D) Regulates Dopaminergic Neuron Loss in Response to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). J. Biol. Chem. 2013, 288 (20), 14362– 14371, DOI: 10.1074/jbc.M112.439216[Crossref], [PubMed], [CAS], Google Scholar344https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvVGktL4%253D&md5=ea76c928074c7162e7d80b1cce784caaPerturbation of transcription factor Nur77 expression mediated by myocyte enhancer factor 2D (MEF2D) regulates dopaminergic neuron Loss in response to 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)Mount, Matthew P.; Zhang, Yi; Amini, Mandana; Callaghan, Steve; Kulczycki, Jerzy; Mao, Zixu; Slack, Ruth S.; Anisman, Hymie; Park, David S.Journal of Biological Chemistry (2013), 288 (20), 14362-14371CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)We have earlier reported the crit. nature of calpain-CDK5-MEF2 signaling in governing dopaminergic neuronal loss in vivo. CDK5 mediates phosphorylation of the neuronal survival factor myocyte enhancer factor 2 (MEF2) leading to its inactivation and loss. However, the downstream factors that mediate MEF2-regulated survival are unknown. Presently, we define Nur77 as one such crit. downstream survival effector. Following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo, Nur77 expression in the nigrostriatal region is dramatically reduced. This loss is attenuated by expression of MEF2. Importantly, MEF2 constitutively binds to the Nur77 promoter in neurons under basal conditions. This binding is lost following 1-methyl-4-phenylpyridinium treatment. Nur77 deficiency results in significant sensitization to dopaminergic loss following 1-methyl-4-phenylpyridinium/MPTP treatment, in vitro and in vivo. Furthermore, Nur77-deficient MPTP-treated mice displayed significantly reduced levels of dopamine and 3,4-Dihydroxyphenylacetic acid in the striatum as well as elevated post synaptic FosB activity, indicative of increased nigrostriatal damage when compared with WT MPTP-treated controls. Importantly, this sensitization in Nur77-deficient mice was rescued with ectopic Nur77 expression in the nigrostriatal system. These results indicate that the inactivation of Nur77, induced by loss of MEF2 activity, plays a crit. role in nigrostriatal degeneration in vivo.
- 341Éthier, I.; Kagechika, H.; Shudo, K.; Rouillard, C.; Lévesque, D. Docosahexaenoic Acid Reduces Haloperidol-Induced Dyskinesias in Mice: Involvement of Nur77 and Retinoid Receptors. Biol. Psychiatry 2004, 56 (7), 522– 526, DOI: 10.1016/j.biopsych.2004.06.036[Crossref], [PubMed], [CAS], Google Scholar345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnvV2ms7o%253D&md5=48225c5fb6a582e72d3caf13c07c005aDocosahexaenoic acid reduces haloperidol-induced dyskinesias in mice: Involvement of Nur77 and retinoid receptorsEthier, Isabelle; Kagechika, Hiroyuki; Shudo, Koichi; Rouillard, Claude; Levesque, DanielBiological Psychiatry (2004), 56 (7), 522-526CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Inc.)Background: Treatment of schizophrenia's symptoms with typical antipsychotic drugs shows some efficacy, but the induction of extrapyramidal symptoms represents a serious handicap, which considerably limits their usefulness. Recent evidence suggests that Nur77 (nerve growth factor-induced B) and retinoids are involved in biochem. and behavioral effects of antipsychotic drugs assocd. with striatal functions. Methods: We evaluated the effect of retinoid ligands on oral dyskinesias (vacuous chewing movements) induced by haloperidol in wild-type and Nur77-deficient mice. Results: Nur77 gene ablation (knockout) or administration of a retinoid antagonist induced vacuous chewing movements and exacerbated those induced by haloperidol, whereas the retinoid agonist docosahexaenoic acid (an ω-3 polyunsatd. fatty acid) reduced them. Both the prodyskinetic effect of the retinoid antagonist and the antidyskinetic effect of docosahexaenoic acid are dependent on the presence of Nur77, since these drugs remained inactive in Nur77 knockout mice. Conclusion: These results suggest that nuclear receptors Nur77 and retinoid X receptor are involved in haloperidol-induced dyskinesias and that retinoid agonists may represent a new way to improve typical antipsychotic drug therapy.
- 342Wei, X.; Gao, H.; Zou, J.; Liu, X.; Chen, D.; Liao, J.; Xu, Y.; Ma, L.; Tang, B.; Zhang, Z.; Cai, X.; Jin, K.; Xia, Y.; Wang, Q. Contra-Directional Coupling of Nur77 and Nurr1 in Neurodegeneration: A Novel Mechanism for Memantine-Induced Anti-Inflammation and Anti-Mitochondrial Impairment. Mol. Neurobiol. 2016, 53 (9), 5876– 5892, DOI: 10.1007/s12035-015-9477-7[Crossref], [PubMed], [CAS], Google Scholar346https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslensL7N&md5=82fa00641dd9edb20a750296adc77691Contra-directional Coupling of Nur77 and Nurr1 in Neurodegeneration: A Novel Mechanism for Memantine-Induced Anti-inflammation and Anti-mitochondrial ImpairmentWei, Xiaobo; Gao, Huimin; Zou, Jing; Liu, Xu; Chen, Dan; Liao, Jinchi; Xu, Yunqi; Ma, Long; Tang, Beisha; Zhang, Zhuohua; Cai, Xiang; Jin, Kunling; Xia, Ying; Wang, QingMolecular Neurobiology (2016), 53 (9), 5876-5892CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Recent evidence suggests that nerve growth factor IB (Nur77) and nuclear receptor related1 (Nurr1) are differentially involved in dopaminergic neurodegeneration. Since memantine has shown clin. relevant efficacy in Parkinson's disease (PD) and displayed a potent protective effect on dopaminergic neurons in exptl. PD models, we asked if it exerts its neuroprotection by regulating Nur77 and Nurr1 signaling. We adopted a well-established in vitro PD model, 6-hydroxydopamine (OHDA)-lesioned PC12 cells, to test our hypothesis. Different concns. of memantine were incubated with 6-OHDA-lesioned PC12 cells, and Nur77/Nurr1 and their related signaling mols. were examd. by Western blot and immunocytochem. Nur77-deficient PC12 cells were used to verify the influences of Nur77 on neurodegeneration and memantine-mediated neuroprotection. We found that memantine reversed Nur77 upregulation and restored Nurr1 downregulation in 6-OHDA-lesioned PC12 cells. 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and induced co-localization of Cyt c/HSP60/Nur77 in the cytosol. Memantine strongly reduced the sub-cellular translocations of Nur77/Cyt c/HSP60 under 6-OHDA-induced oxidative condition. Knockdown of Nur77 enhanced the viability of PC12 cells exposed to 6-OHDA, while memantine-induced neuroprotection was much less in the cells with Nur77 knockdown than in those without it. We conclude that Nur77 plays a crucial role in modulating mitochondrial impairment and contributes to neurodegeneration under the exptl. PD condition. Memantine effectively suppresses such Nur77-mediated neurodegeneration and promotes survival signaling through post-translational modification of Nurr1. Nur77 and Nurr1 present a contra-directionally coupling interaction in memantine-mediated neuroprotection.
- 343Popichak, K. A.; Hammond, S. L.; Moreno, J. A.; Afzali, M. F.; Backos, D. S.; Slayden, R. D.; Safe, S.; Tjalkens, R. B. Compensatory Expression of NuR77 and NURR1 Regulates NF-KB–Dependent Inflammatory Signaling in Astrocytes. Mol. Pharmacol. 2018, 94 (4), 1174– 1186, DOI: 10.1124/mol.118.112631[Crossref], [PubMed], [CAS], Google Scholar347https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVGgt7nF&md5=07bcd618fd1eeabc599b889f137eb1bdCompensatory expression of Nur77 and Nurr1 regulates NF-KB-dependent inflammatory signaling in astrocytesPopichak, Katriana A.; Hammond, Sean L.; Moreno, Julie A.; Afzali, Maryam F.; Backos, Donald S.; Slayden, Richard D.; Safe, Stephen; Tjalkens, Ronald B.Molecular Pharmacology (2018), 94 (4), 1174-1186CODEN: MOPMA3; ISSN:1521-0111. (American Society for Pharmacology and Experimental Therapeutics)We postulated that a recently developed NR4A receptor ligand, 1,1bis (3'indolyl) 1(pmethoxyphenyl) methane (C-DIM5), would suppress NF-KB-dependent inflammatory gene expression in astrocytes after treatment with 1-methyl-4-Ph 1, 2, 3, 6-tetrahydropyridine (MPTP) and the inflammatory cytokines interferon gamma and tumor necrosis factor a. C-DIM5 increased expression of Nur77 mRNA and suppressed expression ofmultiple neuroinflammatory genes. C-DIM5 also inhibited the expression of NFKB-regulated inflammatory and apoptotic genes in quant. polymerase chain reaction array studies and effected p65 binding to unique genes in chromatin immunopptn. next-generation sequencing expts. but did not prevent p65 translocation to the nucleus, suggesting a nuclear-specific mechanism. C-DIM5 prevented nuclear export of Nur77 in astrocytes induced by MPTP treatment and simultaneously recruited Nurr1 to the nucleus, consistent with known transrepressive properties of this receptor. Combined RNAi knockdown of Nur77 and Nurr1 inhibited the anti-inflammatory activity of C-DIM5, demonstrating that C-DIM5 requires these receptors to inhibit NF-KB. Collectively, these data demonstrate that NR4A1/Nur77 and NR4A2/Nurr1 dynamically regulated inflammatory gene expression in glia by modulating the transcriptional activity of NF-KB.
- 344Liu, T.-Y.; Yang, X.-Y.; Zheng, L.-T.; Wang, G.-H.; Zhen, X.-C. Activation of Nur77 in Microglia Attenuates Proinflammatory Mediators Production and Protects Dopaminergic Neurons from Inflammation-Induced Cell Death. J. Neurochem. 2017, 140 (4), 589– 604, DOI: 10.1111/jnc.13907[Crossref], [PubMed], [CAS], Google Scholar348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFWlsbbE&md5=c8ea37e76cdb97d5984ea9ddd73de629Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation-induced cell deathLiu, Tian-Ya; Yang, Xiao-Ying; Zheng, Long-Tai; Wang, Guang-Hui; Zhen, Xue-ChuJournal of Neurochemistry (2017), 140 (4), 589-604CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)Microglia-mediated neuroinflammation plays a crit. role in the pathol. development of Parkinson's disease (PD). Orphan nuclear receptor Nur77 is abundant in neurons, while its role in microglia-mediated neuroinflammation remains unclear. The present data demonstrated that the expression of Nur77 in microglia was reduced accompanied by microglia activation in response to lipopolysaccharide (LPS) in vitro and in exptl. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model. Nur77 over-expression or application of Nur77 agonist cytosporone B suppressed the expression of proinflammatory genes, such as inducible nitric oxide NOS, cyclooxygenase-2, IL-1β, and tumor necrosis factor-α in the activated microglia, while silenced Nur77 exaggerated the inflammatory responses in microglia. Moreover, activation of Nur77 suppressed the LPS-induced NF-κB activation which was partly dependent on p38 MAPK activity, since inhibition of p38 MAPK by SB203580 abolished the LPS-activated NF-κB in microglia. On the other hand, inhibition of p38 MAPK attenuated LPS-induced Nur77 redn. Furthermore, in a microglia-conditioned cultured media system, Nur77 ameliorated the cytotoxicity to MN9D dopaminergic cells. Lastly, cytosporone B attenuated microglia activation and loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model. Taken together, these findings revealed the first evidence that Nur77 was an important modulator in microglia function that assocd. with microglia-mediated dopaminergic neurotoxicity, and thus modulation of Nur77 may represent a potential novel target for treatment for neurodegenerative disease.
- 345Yan, J.; Huang, J.; Wu, J.; Fan, H.; Liu, A.; Qiao, L.; Shen, M.; Lai, X. Nur77 Attenuates Inflammatory Responses and Oxidative Stress by Inhibiting Phosphorylated IκB-α in Parkinson’s Disease Cell Model. Aging 2020, 12 (9), 8107– 8119, DOI: 10.18632/aging.103128[Crossref], [PubMed], [CAS], Google Scholar349https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFagurzN&md5=11c7b47b77d171378382d3590bfb410eNur77 attenuates inflammatory responses and oxidative stress by inhibiting phosphorylated IκB-α in Parkinson's disease cell modelYan, Junqiang; Huang, Jiarui; Wu, Jiannan; Fan, Hua; Liu, Anran; Qiao, Liang; Shen, Mengmeng; Lai, XiaoyiAging (2020), 12 (9), 8107-8119CODEN: AGINCN; ISSN:1945-4589. (Impact Journals LLC)Neuroinflammation and oxidative stress play key roles in the pathol. development of Parkinson's disease (PD). Nerve growth factor-induced gene B (Nur77) is closely related to dopamine neurotransmission, and its pathogenesis is unclear. This study aims to investigate the role and mechanism of Nur77 in a cell model of Parkinson's disease. Silencing Nur77 with siRNA can aggravate intracellular LDH release, increase the expression of pro-inflammatory genes (such as tumor necrosis factor a, nuclear factor κB (p65), monocyte chemotactic protein 1, interleukin-6), and decrease cell survival, decrease expression of nuclear factor E2-related factor(Nrf2), heme oxygenase 1, NADPH quinineoxidoreductase-1. Cytosporone B (Nur77 agonist) has the opposite effect to Nur77 silencing. PDTC (NF-κB inhibitor / antioxidant) can also inhibit pro-inflammatory genes to a similar degree as Cytosporone B. Phosphorylated IκB-α can be inhibited by Cytosporone B, while silencing Nur77 can increase the protein expression level of phosphorylated IκB-α. After silencing IκB-α, both Cytosporone B and siNur77 did not affect pro-inflammatory genes and antioxidant stress. These findings reveal the first evidence that Nur77 exerts anti-inflammatory and antioxidant stress effects by inhibiting IκB-α phosphorylation expression in a Parkinson cell model. Nur77 may be a potential therapeutic target for Parkinson's disease.
- 346Liebmann, M.; Hucke, S.; Koch, K.; Eschborn, M.; Ghelman, J.; Chasan, A. I.; Glander, S.; Schädlich, M.; Kuhlencord, M.; Daber, N. M.; Eveslage, M.; Beyer, M.; Dietrich, M.; Albrecht, P.; Stoll, M.; Busch, K. B.; Wiendl, H.; Roth, J.; Kuhlmann, T.; Klotz, L. Nur77 Serves as a Molecular Brake of the Metabolic Switch during T Cell Activation to Restrict Autoimmunity. Proc. Natl. Acad. Sci. U. S. A. 2018, 115 (34), E8017– E8026, DOI: 10.1073/pnas.1721049115[Crossref], [PubMed], [CAS], Google Scholar350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVCitLbK&md5=305091a88d2683a65f1407cf575acfe3Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunityLiebmann, Marie; Hucke, Stephanie; Koch, Kathrin; Eschborn, Melanie; Ghelman, Julia; Chasan, Achmet I.; Glander, Shirin; SchAdlich, Martin; Kuhlencord, Meike; Daber, Niklas M.; Eveslage, Maria; Beyer, Marc; Dietrich, Michael; Albrecht, Philipp; Stoll, Monika; Busch, Karin B.; Wiendl, Heinz; Roth, Johannes; Kuhlmann, Tanja; Klotz, LuisaProceedings of the National Academy of Sciences of the United States of America (2018), 115 (34), E8017-E8026CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)T cells critically depend on reprogramming of metabolic signatures to meet the bioenergetic demands during activation and clonal expansion. Here we identify the transcription factor Nur77 as a cell-intrinsic modulator of T cell activation. Nur77-deficient T cells are highly proliferative, and lack of Nur77 is assocd. with enhanced T cell activation and increased susceptibility for T cell-mediated inflammatory diseases, such as CNS autoimmunity, allergic contact dermatitis and collagen-induced arthritis. Importantly, Nur77 serves as key regulator of energy metab. in T cells, restricting mitochondrial respiration and glycolysis and controlling switching between different energy pathways. Transcriptional network anal. revealed that Nur77 modulates the expression of metabolic genes, most likely in close interaction with other transcription factors, esp. estrogen-related receptor α. In summary, we identify Nur77 as a transcriptional regulator of T cell metab., which elevates the threshold for T cell activation and confers protection in different T cell-mediated inflammatory diseases.
- 347Rothe, T.; Ipseiz, N.; Faas, M.; Lang, S.; Perez-Branguli, F.; Metzger, D.; Ichinose, H.; Winner, B.; Schett, G.; Krönke, G. The Nuclear Receptor Nr4a1 Acts as a Microglia Rheostat and Serves as a Therapeutic Target in Autoimmune-Driven Central Nervous System Inflammation. J. Immunol. 2017, 198 (10), 3878– 3885, DOI: 10.4049/jimmunol.1600638[Crossref], [PubMed], [CAS], Google Scholar351https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXns1SktLY%253D&md5=ec349e37553ce84b464e3f4bd496d4f4The Nuclear Receptor Nr4a1 Acts as a Microglia Rheostat and Serves as a Therapeutic Target in Autoimmune-Driven Central Nervous System InflammationRothe, Tobias; Ipseiz, Natacha; Faas, Maria; Lang, Stefanie; Perez-Branguli, Francesc; Metzger, Daniel; Ichinose, Hiroshi; Winner, Beate; Schett, Georg; Kroenke, GerhardJournal of Immunology (2017), 198 (10), 3878-3885CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)Microglia cells fulfill key homeostatic functions and essentially contribute to host defense within the CNS. Altered activation of microglia, in turn, has been implicated in neuroinflammatory and neurodegenerative diseases. In this study, we identify the nuclear receptor (NR) Nr4a1 as key rheostat controlling the activation threshold and polarization of microglia. In steady-state microglia, ubiquitous neuronal-derived stress signals such as ATP induced expression of this NR, which contributed to the maintenance of a resting and noninflammatory microglia phenotype. Global and microglia-specific deletion of Nr4a1 triggered the spontaneous and overwhelming activation of microglia and resulted in increased cytokine and NO prodn. as well as in an accelerated and exacerbated form of exptl. autoimmune encephalomyelitis. Ligand-induced activation of Nr4a1 accordingly ameliorated the course of this disease. Our current data thus identify Nr4a1 as regulator of microglia activation and potentially new target for the treatment of inflammatory CNS diseases such as multiple sclerosis.
- 348Zhao, Y.; Liu, Y.; Zheng, D. Alpha 1-Antichymotrypsin/SerpinA3 Is a Novel Target of Orphan Nuclear Receptor Nur77. FEBS J. 2008, 275 (5), 1025– 1038, DOI: 10.1111/j.1742-4658.2008.06269.x[Crossref], [PubMed], [CAS], Google Scholar352https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXivFaqtbs%253D&md5=077966f45d92e1f3f376c9cc6919fc4dAlpha 1-antichymotrypsin/SerpinA3 is a novel target of orphan nuclear receptor Nur77Zhao, Yongjuan; Liu, Yanxin; Zheng, DexianFEBS Journal (2008), 275 (5), 1025-1038CODEN: FJEOAC; ISSN:1742-464X. (Blackwell Publishing Ltd.)Nur77 is one member of the nuclear receptor superfamily. As a transcription factor, Nur77 participates in a variety of biol. processes, including T cell development, inflammatory responses, steroid hormone synthesis, and hepatic glucose metab. It typically acts via binding to the Nur77 responsive element (NBRE) in the promoter regions of its target genes. In the present study, we identified a novel Nur77-regulated gene, α1-antichymotrypsin/SerpinA3, via an approach combining computational prediction and wet-lab. validations. First, we identified 483 candidate genes via a human genome-wide scan for NBREs in their proximal promoters. Three out of 14 function-assocd. genes were further identified to be trans-activated by Nur77 in luciferase reporter gene assays in HEK 293T cells. The transactivation assay proved that the NBRE (-182 to -175) in the SerpinA3 promoter region is a novel Nur77-dependent functional motif in HEK 293T and HepG2 cells. Electrophoretic mobility shift and chromatin immunopptn. assays demonstrated that Nur77 phys. assocs. with the SerpinA3 promoter region both in vitro and in vivo. Nur77 overexpression and RNA interference-mediated Nur77 gene knockdown anal. confirmed that SerpinA3 is indeed a novel Nur77-targeted gene. These data may throw light on the function of Nur77 in inflammatory responses and acute-phase reactions as well as the development of Alzheimer's disease.
- 349Wang, L.; Zheng, Y.; Gao, X.; Liu, Y.; You, X. Retinoid X Receptor Ligand Regulates RXRα/Nur77-Dependent Apoptosis via Modulating Its Nuclear Export and Mitochondrial Targeting. Int. J. Clin. Exp. Pathol. 2017, 10 (11), 10770– 10780[PubMed], [CAS], Google Scholar353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38%252FivFynsA%253D%253D&md5=a3714587a04eebc300604affa6a6426cRetinoid X receptor ligand regulates RXRα/Nur77-dependent apoptosis via modulating its nuclear export and mitochondrial targetingWang Li; Gao Xiaoxiao; Liu Yingchun; You Xiaoqing; Zheng YansongInternational journal of clinical and experimental pathology (2017), 10 (11), 10770-10780 ISSN:.Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder disease in elderly. It is characterized by the formation of amyloid plaques and nerve cells apoptosis in the brain. This study focuses on the association between nerve cells apoptosis and nuclear receptors within AD. Thus, we detected the changes of the expression and subcellular localization of RXRα/Nur77 and the apoptotic rate of neuroblastoma cells, SH-SY5Y cells and nerve cells in C57BL/6 mouse hippocampus in Alzheimer's disease pathologic condition, and investigated the effect of RXRα exporting inhibition caused by 9-cis-RA on the apoptosis of neurons. We demonstrated that Aβ peptide and H2O2 treatment could result in the translocation of RXRα and Nur77 from the nucleus to the mitochondria, and the ligand of RXR, 9-cis-RA, treatment can block the above phenomenon. More importantly, 9-cis-RA treatment could reduce the apoptotic rate of neurons caused by H2O2 or Aβ stimulation via enhancing the expression level of Bcl-2 protein. Therefore, our studies revealed a critical role of RXRα/Nur77 in 9-cis-RA-mediated anti-apoptosis in nerve cells and provided novel information for better management of AD.
- 350Zhan, Y.; Du, X.; Chen, H.; Liu, J.; Zhao, B.; Huang, D.; Li, G.; Xu, Q.; Zhang, M.; Weimer, B. C.; Chen, D.; Cheng, Z.; Zhang, L.; Li, Q.; Li, S.; Zheng, Z.; Song, S.; Huang, Y.; Ye, Z.; Su, W.; Lin, S.-C.; Shen, Y.; Wu, Q. Cytosporone B Is an Agonist for Nuclear Orphan Receptor Nur77. Nat. Chem. Biol. 2008, 4 (9), 548– 556, DOI: 10.1038/nchembio.106[Crossref], [PubMed], [CAS], Google Scholar354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpvFGrt7g%253D&md5=0514b5b3d32810b2de3b0218479e23f7Cytosporone B is an agonist for nuclear orphan receptor Nur77Zhan, Yanyan; Du, Xiping; Chen, Hangzi; Liu, Jingjing; Zhao, Bixing; Huang, Danhong; Li, Guideng; Xu, Qingyan; Zhang, Mingqing; Weimer, Bart C.; Chen, Dong; Cheng, Zhe; Zhang, Lianru; Li, Qinxi; Li, Shaowei; Zheng, Zhonghui; Song, Siyang; Huang, Yaojian; Ye, Zhiyun; Su, Wenjin; Lin, Sheng-Cai; Shen, Yuemao; Wu, QiaoNature Chemical Biology (2008), 4 (9), 548-556CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Nuclear orphan receptor Nur77 has important roles in many biol. processes. However, a physiol. ligand for Nur77 has not been identified. Here, we report that the octaketide cytosporone B (Csn-B) is a naturally occurring agonist for Nur77. Csn-B specifically binds to the ligand-binding domain of Nur77 and stimulates Nur77-dependent transactivational activity towards target genes including Nr4a1 (Nur77) itself, which contains multiple consensus response elements allowing pos. autoregulation in a Csn-B-dependent manner. Csn-B also elevates blood glucose levels in fasting C57 mice, an effect that is accompanied by induction of multiple genes involved in gluconeogenesis. These biol. effects were not obsd. in Nur77-null (Nr4a1-/-) mice, which indicates that Csn-B regulates gluconeogenesis through Nur77. Moreover, Csn-B induced apoptosis and retarded xenograft tumor growth by inducing Nur77 expression, translocating Nur77 to mitochondria to cause cytochrome c release. Thus, Csn-B may represent a promising therapeutic drug for cancers and hypoglycemia, and it may also be useful as a reagent to increase understanding of Nur77 biol. function.
- 351Munoz-Tello, P.; Lin, H.; Khan, P.; De Vera, I. M. S.; Kamenecka, T. M.; Kojetin, D. J. Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1. J. Med. Chem. 2020, 63 (24), 15639– 15654, DOI: 10.1021/acs.jmedchem.0c00894[ACS Full Text], [CAS], Google Scholar355https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFShsrzL&md5=6f76ae9c9cb563d7e4ed80989366acc4Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1Munoz-Tello, Paola; Lin, Hua; Khan, Pasha; de Vera, Ian Mitchelle S.; Kamenecka, Theodore M.; Kojetin, Douglas J.Journal of Medicinal Chemistry (2020), 63 (24), 15639-15654CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Nurr1/NR4A2 is an orphan nuclear receptor transcription factor implicated as a drug target for neurol. disorders including Alzheimer's and Parkinson's diseases. Previous studies identified small-mol. NR4A nuclear receptor modulators, but it remains unclear if these ligands affect transcription via direct binding to Nurr1. We assessed 12 ligands reported to affect NR4A activity for Nurr1-dependent and Nurr1-independent transcriptional effects and the ability to bind the Nurr1 ligand-binding domain (LBD). Protein NMR structural footprinting data show that amodiaquine, chloroquine, and cytosporone B bind the Nurr1 LBD; ligands that do not bind include C-DIM12, celastrol, camptothecin, IP7e, isoalantolactone, Et 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), and three high-throughput screening hit derivs. Importantly, ligands that modulate Nurr1 transcription also show Nurr1-independent effects on transcription in a cell type-specific manner, indicating that care should be taken when interpreting the functional response of these ligands in transcriptional assays. These findings should help focus medicinal chem. efforts that desire to optimize Nurr1-binding ligands.
- 352Liu, J.-J.; Zeng, H.-N.; Zhang, L.-R.; Zhan, Y.-Y.; Chen, Y.; Wang, Y.; Wang, J.; Xiang, S.-H.; Liu, W.-J.; Wang, W.-J.; Chen, H.-Z.; Shen, Y.-M.; Su, W.-J.; Huang, P.-Q.; Zhang, H.-K.; Wu, Q. A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In Vivo and In Vitro. Cancer Res. 2010, 70 (9), 3628– 3637, DOI: 10.1158/0008-5472.CAN-09-3160[Crossref], [PubMed], [CAS], Google Scholar356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXltlens7w%253D&md5=ef78038604088d871c376495a9b978c7A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In vivo and In vitroLiu, Jing-jing; Zeng, Hui-ni; Zhang, Lian-ru; Zhan, Yan-yan; Chen, Yan; Wang, Yuan; Wang, Juan; Xiang, Shao-hua; Liu, Wen-jun; Wang, Wei-jia; Chen, Hang-zi; Shen, Yue-mao; Su, Wen-jin; Huang, Pei-qiang; Zhang, Hong-kui; Wu, QiaoCancer Research (2010), 70 (9), 3628-3637CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Nur77 is a steroid orphan receptor that plays a crit. role in regulating proliferation, differentiation, and apoptosis, including acting as a switch for Bcl-2 function. We previously reported that the octaketide cytosporone B (Csn-B) is a natural agonist for Nur77. In this study, we synthesized a series of Csn-B analogs and performed a structure-activity anal. that suggested criteria for the development of a unique pharmacophore to activate Nur77. The components of the pharmacophore necessary for binding Nur77 included the benzene ring, the phenolic hydroxyl group, and the acyl chain of the Csn-B scaffold, whereas the key feature for activating the biol. function of Nur77 was the ester group. Csn-B analogs that bound Nur77 tightly not only stimulated its transactivation activity but also initiated mitochondrial apoptosis by means of novel cross-talk between Nur77 and BRE, an antiapoptotic protein regulated at the transcriptional level. Notably, the deriv. n-amyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl]acetate exhibited greater antitumor activity in vivo than its parent compds., highlighting particular interest in this compd. Our findings describe a pathway for rational design of Csn-B-derived Nur77 agonists as a new class of potent and effective antitumor agents. Cancer Res; 70(9); 3628-37.
- 353Yang, P.-B.; Hou, P.-P.; Liu, F.-Y.; Hong, W.-B.; Chen, H.-Z.; Sun, X.-Y.; Li, P.; Zhang, Y.; Ju, C.-Y.; Luo, L.-J.; Wu, S.-F.; Zhou, J.-X.; Wang, Z.-J.; He, J.-P.; Li, L.; Zhao, T.-J.; Deng, X.; Lin, T.; Wu, Q. Blocking PPARγ Interaction Facilitates Nur77 Interdiction of Fatty Acid Uptake and Suppresses Breast Cancer Progression. Proc. Natl. Acad. Sci. U. S. A. 2020, 117 (44), 27412– 27422, DOI: 10.1073/pnas.2002997117[Crossref], [PubMed], [CAS], Google Scholar357https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1Ghu7vN&md5=50e8290033350110d998d4d65aebb89bBlocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progressionYang, Peng-bo; Hou, Pei-pei; Liu, Fu-yuan; Hong, Wen-bin; Chen, Hang-zi; Sun, Xiao-yu; Li, Peng; Zhang, Yi; Ju, Cui-yu; Luo, Li-juan; Wu, Sheng-fu; Zhou, Jia-xin; Wang, Zhi-jing; He, Jian-ping; Li, Li; Zhao, Tong-Jin; Deng, Xianming; Lin, Tianwei; Wu, QiaoProceedings of the National Academy of Sciences of the United States of America (2020), 117 (44), 27412-27422CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigenesis. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degrdn. of Nur77. Cocrystallog. and functional anal. revealed that Csn-B, a Nur77-targeting compd., promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77's inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.
- 354Wang, W.; Wang, Y.; Chen, H.; Xing, Y.; Li, F.; Zhang, Q.; Zhou, B.; Zhang, H.; Zhang, J.; Bian, X.; Li, L.; Liu, Y.; Zhao, B.; Chen, Y.; Wu, R.; Li, A.; Yao, L.; Chen, P.; Zhang, Y.; Tian, X.; Beermann, F.; Wu, M.; Han, J.; Huang, P.; Lin, T.; Wu, Q. Orphan Nuclear Receptor TR3 Acts in Autophagic Cell Death via Mitochondrial Signaling Pathway. Nat. Chem. Biol. 2014, 10 (2), 133– 140, DOI: 10.1038/nchembio.1406[Crossref], [PubMed], [CAS], Google Scholar358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvV2hsLrM&md5=cc674e5fe1c3126f82b5749a8588c24bOrphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathwayWang, Wei-jia; Wang, Yuan; Chen, Hang-zi; Xing, Yong-zhen; Li, Feng-wei; Zhang, Qian; Zhou, Bo; Zhang, Hong-kui; Zhang, Jie; Bian, Xue-li; Li, Li; Liu, Yuan; Zhao, Bi-xing; Chen, Yan; Wu, Rong; Li, An-zhong; Yao, Lu-ming; Chen, Ping; Zhang, Yi; Tian, Xu-yang; Beermann, Friedrich; Wu, Mian; Han, Jiahuai; Huang, Pei-qiang; Lin, Tianwei; Wu, QiaoNature Chemical Biology (2014), 10 (2), 133-140CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Autophagy is linked to cell death, yet the assocd. mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of mol. events leading to cellular demise is launched by a specific chem. compd., 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.
- 355Wang, W.; Wang, Y.; Hou, P.-P.; Li, F.-W.; Zhou, B.; Chen, H.-Z.; Bian, X.-L.; Cai, Q.-X.; Xing, Y.-Z.; He, J.-P.; Zhang, H.; Huang, P.-Q.; Lin, T.; Wu, Q. Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity. Chem. Biol. 2015, 22 (8), 1040– 1051, DOI: 10.1016/j.chembiol.2015.06.023[Crossref], [PubMed], [CAS], Google Scholar359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KmtbbK&md5=9f18c8c678d2620b437d9f3c4ab1696aInduction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 ActivityWang, Wei-jia; Wang, Yuan; Hou, Pei-pei; Li, Feng-wei; Zhou, Bo; Chen, Hang-zi; Bian, Xue-li; Cai, Qi-xu; Xing, Yong-zhen; He, Jian-ping; Zhang, Hongkui; Huang, Pei-qiang; Lin, Tianwei; Wu, QiaoChemistry & Biology (Oxford, United Kingdom) (2015), 22 (8), 1040-1051CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)Apoptotic resistance is becoming a significant obstacle for cancer therapy as the majority of treatment takes the route of apoptotic induction. It is of great importance to develop an alternative strategy to induce cancer cell death. We previously reported that autophagic cell death mediated by nuclear receptor TR3 and driven by a chem. agonist, 1-(3,4,5-trihydroxyphenyl)nonan-1-one (THPN), is highly effective in the therapy of melanoma but not any other cancer types. Here, we discovered that the insensitivity of cancer cells to THPN originated from a high cellular Akt2 activity. Akt2 phosphorylation interferes with TR3 export to cytoplasm and targeting to mitochondria, which lead to the autophagic induction. Therefore, the TR3-mediated autophagy could be effectively induced in the otherwise insensitive cells by downregulating Akt2 activity. Highly effective antineoplastic compds. are developed through optimizing the structure of THPN. This study implicates a general strategy for cancer therapy by the induction of autophagic cell death.
- 356Hu, M.; Luo, Q.; Alitongbieke, G.; Chong, S.; Xu, C.; Xie, L.; Chen, X.; Zhang, D.; Zhou, Y.; Wang, Z.; Ye, X.; Cai, L.; Zhang, F.; Chen, H.; Jiang, F.; Fang, H.; Yang, S.; Liu, J.; Diaz-Meco, M. T.; Su, Y.; Zhou, H.; Moscat, J.; Lin, X.; Zhang, X.-K. Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy. Mol. Cell 2017, 66 (1), 141– 153, DOI: 10.1016/j.molcel.2017.03.008[Crossref], [PubMed], [CAS], Google Scholar360https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvFWgs7s%253D&md5=a8efd7d1312b3252511ad4d8cd8db045Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and AutophagyHu, Mengjie; Luo, Qiang; Alitongbieke, Gulimiran; Chong, Shuyi; Xu, Chenting; Xie, Lei; Chen, Xiaohui; Zhang, Duo; Zhou, Yuqi; Wang, Zhaokai; Ye, Xiaohong; Cai, Lijun; Zhang, Fang; Chen, Huibin; Jiang, Fuquan; Fang, Hui; Yang, Shanjun; Liu, Jie; Diaz-Meco, Maria T.; Su, Ying; Zhou, Hu; Moscat, Jorge; Lin, Xiangzhi; Zhang, Xiao-kunMolecular Cell (2017), 66 (1), 141-153.e6CODEN: MOCEFL; ISSN:1097-2765. (Elsevier Inc.)Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-assocd. factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a crit. intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.
- 357Jung, Y.-S.; Lee, H.-S.; Cho, H.-R.; Kim, K.-J.; Kim, J.-H.; Safe, S.; Lee, S.-O. Dual Targeting of Nur77 and AMPKα by Isoalantolactone Inhibits Adipogenesis in Vitro and Decreases Body Fat Mass in Vivo. Int. J. Obes. 2019, 43 (5), 952– 962, DOI: 10.1038/s41366-018-0276-x[Crossref], [CAS], Google Scholar361https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFSms7fP&md5=7e9eab7cc05227ff49cf98e8cf957bc7Dual targeting of Nur77 and AMPKα by isoalantolactone inhibits adipogenesis in vitro and decreases body fat mass in vivoJung, Yeon-Seop; Lee, Hyo-Seon; Cho, Hye-Rin; Kim, Keuk-Jun; Kim, Joung-Hee; Safe, Stephen; Lee, Syng-OokInternational Journal of Obesity (2019), 43 (5), 952-962CODEN: IJOBDP; ISSN:0307-0565. (Nature Research)Background: Suppression of adipogenesis has been considered as a potential target for the prevention and treatment of obesity and assocd. metabolic disorders, and the nuclear receptor 4A1 (NR4A1/Nur77) and AMPKα are known to play important roles during early and intermediate stages of adipogenesis. Therefore, we hypothesized that dual targeting Nur77 and AMPKα would show strong inhibitory effect on adipogenesis. Methods: We screened a herbal medicine-based small mol. library to identify novel natural compds. dual targeting Nur77 and AMPKα, and the antiadipogenic effects and mechanisms of action of a "hit" compd. were studied in 3T3-L1 cells. In vivo antiobesity effects of the compd. were also investigated in high-fat diet (HFD)-induced obese mice. Results: We identified isoalantolactone (ISO) as a new NR4A1 inactivator that also activates AMPKα in 3T3-L1 cells. ISO, as expected, inhibited adipogenic differentiation of 3T3-L1 preadipocytes, accompanied by reduced mitotic clonal expansion (MCE) which occurs in the early stage of adipogenesis and decreased expression of genes required for MCE and cell cycle markers including cyclin A, cyclin D1. Furthermore, ISO reduced body wt. gain and fat mass (epididymal, s.c., perirenal, and inguinal white adipose tissues) in the high-fat diet-fed C57BL/6 N mice. Serum levels of triglycerides, aspartate transaminase, and alanine transaminase and hepatic steatosis were also significantly improved in the ISO-treated group compared to the high-fat diet control group. Conclusions: These results suggest that ISO dual targeting Nur77 and AMPKα during adipogenesis represents a novel class of mechanism-based antiadipogenic agents for treatment of obesity and assocd. metabolic disorders, including hyperlipidemia and fatty liver.
- 358Vinayavekhin, N.; Saghatelian, A. Discovery of a Protein-Metabolite Interaction between Unsaturated Fatty Acids and the Nuclear Receptor Nur77 Using a Metabolomics Approach. J. Am. Chem. Soc. 2011, 133 (43), 17168– 17171, DOI: 10.1021/ja208199h[ACS Full Text], [CAS], Google Scholar362https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1OnsbrJ&md5=4b50bc3a70cedccb6c188aa7959c0769Discovery of a Protein-Metabolite Interaction between Unsaturated Fatty Acids and the Nuclear Receptor Nur77 Using a Metabolomics ApproachVinayavekhin, Nawaporn; Saghatelian, AlanJournal of the American Chemical Society (2011), 133 (43), 17168-17171CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Neuron-derived clone 77 (Nur77) is an orphan nuclear receptor with currently no known natural ligands. Here we applied a metabolomics platform for detecting protein-metabolite interactions (PMIs) to identify lipids that bind to Nur77. Using this approach, we discovered that the Nur77 ligand-binding domain (Nur77LBD) enriches unsatd. fatty acids (UFAs) in tissue lipid mixts. The interaction of Nur77 with arachidonic acid and docosahexaenoic acid was subsequently characterized using a no. of biophys. and biochem. assays. Together these data indicate that UFAs bind to Nur77LBD to cause changes in the conformation and oligomerization of the receptor. UFAs are the only endogenous lipids reported to bind to Nur77, which highlights the use of metabolomics in the discovery of novel PMIs.
- 359Lakshmi, S. P.; Reddy, A. T.; Banno, A.; Reddy, R. C. Molecular, Chemical, and Structural Characterization of Prostaglandin A2 as a Novel Agonist for Nur77. Biochem. J. 2019, 476 (19), 2757– 2767, DOI: 10.1042/BCJ20190253[Crossref], [PubMed], [CAS], Google Scholar363https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlCks7rJ&md5=990368ac30502c102198dffa73c56c76Molecular, chemical, and structural characterization of prostaglandin A2 as a novel agonist for Nur77Lakshmi, Sowmya P.; Reddy, Aravind T.; Banno, Asoka; Reddy, Raju C.Biochemical Journal (2019), 476 (19), 2757-2767CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)Prior research that revealed a structurally atypical ligand-binding domain (LBD) and failed to locate an endogenous ligand had led to a classification of Nur77 as an orphan receptor. However, several more recent studies indicate that small synthetic mols. and unsatd. fatty acids can bind to Nur77. Discovery of addnl. endogenous ligands will facilitate our understanding of the receptor's functions and regulatory mechanisms. Our data have identified prostaglandin A2 (PGA2), a cyclopentenone prostaglandin (PG), as such a ligand. Cyclopentenone PGs exert their biol. effects primarily by forming protein adducts via the characteristic electrophilic beta-carbon(s) located in their cyclopentenone rings. Our data show that PGA2 induces Nur77 transcriptional activity by forming a covalent adduct between its endocyclic β-carbon, C9, and Cys566 in the receptor's LBD. The importance of this endocyclic β-carbon was substantiated by the failure of PGs without such electrophilic properties to react with Nur77. Calcd. chem. properties and data from reactive mol. dynamic simulations, intrinsic reaction coordinate modeling, and covalent mol. docking also corroborate the selectivity of PGA2's C9 β-carbon towards Nur77's Cys. In summary, our mol., chem., and structural characterization of the PGA2-Nur77 interaction provides the first evidence that PGA2 is an endogenous Nur77 agonist.
- 360Willems, S.; Kilu, W.; Ni, X.; Chaikuad, A.; Knapp, S.; Heering, J.; Merk, D. The Orphan Nuclear Receptor Nurr1 Is Responsive to Non-Steroidal Anti-Inflammatory Drugs. Commun. Chem. 2020, 3 (1), 85, DOI: 10.1038/s42004-020-0331-0[Crossref], [CAS], Google Scholar364https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVKksrvE&md5=780001615544ae3f93a28007f8f492beThe orphan nuclear receptor Nurr1 is responsive to non-steroidal anti-inflammatory drugsWillems, Sabine; Kilu, Whitney; Ni, Xiaomin; Chaikuad, Apirat; Knapp, Stefan; Heering, Jan; Merk, DanielCommunications Chemistry (2020), 3 (1), 85CODEN: CCOHCT; ISSN:2399-3669. (Nature Research)Nuclear receptor related 1 (Nurr1) is an orphan ligand-activated transcription factor and considered as neuroprotective transcriptional regulator with great potential as therapeutic target for neurodegenerative diseases. However, the collection of available Nurr1 modulators and mechanistic understanding of Nurr1 are limited. Here, we report the discovery of several structurally diverse non-steroidal anti-inflammatory drugs as inverse Nurr1 agonists demonstrating that Nurr1 activity can be regulated bidirectionally. As chem. tools, these ligands enable unraveling the co-regulatory network of Nurr1 and the mode of action distinguishing agonists from inverse agonists. In addn. to its ability to dimerize, we observe an ability of Nurr1 to recruit several canonical nuclear receptor co-regulators in a ligand-dependent fashion. Distinct dimerization states and co-regulator interaction patterns arise as discriminating factors of Nurr1 agonists and inverse agonists. Our results contribute a valuable collection of Nurr1 modulators and relevant mechanistic insights for future Nurr1 target validation and drug discovery.
- 361Ordentlich, P.; Yan, Y.; Zhou, S.; Heyman, R. A. Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1. J. Biol. Chem. 2003, 278 (27), 24791– 24799, DOI: 10.1074/jbc.M302167200[Crossref], [PubMed], [CAS], Google Scholar365https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltVSlsrY%253D&md5=14ff5059d95ea70552781473d260d340Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1Ordentlich, Peter; Yan, Yingzhuo; Zhou, Sihong; Heyman, Richard A.Journal of Biological Chemistry (2003), 278 (27), 24791-24799CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The purine anti-metabolite 6-mercaptopurine is one of the most widely used drugs for the treatment of acute childhood leukemia and chronic myelocytic leukemia. Developed in the 1950s, the drug is also being used as a treatment for inflammatory diseases such as Crohn's disease. The antiproliferative mechanism of action of this drug and other purine anti-metabolites has been demonstrated to be through inhibition of de novo purine synthesis and incorporation into nucleic acids. Despite the extensive clin. use and study of 6-mercaptopurine and other purine analogs, the cellular effects of these compds. remain relatively unknown. More recently, purine anti-metabolites have been shown to function as protein kinase inhibitors and to regulate gene expression. In an attempt to find small mol. regulators of the orphan nuclear receptor Nurr1, interestingly, we identified 6-mercaptopurine as a specific activator of this receptor. A detailed anal. of 6-mercaptopurine regulation of Nurr1 demonstrates that 6-mercaptopurine regulates Nurr1 through a region in the amino terminus. This activity can be inhibited by components of the purine biosynthesis pathway. These findings indicate that Nurr1 may play a role in mediating some of the antiproliferative effects of 6-mercaptopurine and potentially implicate Nurr1 as a mol. target for treatment of leukemias.
- 362Wansa, K. D. S. A.; Harris, J. M.; Yan, G.; Ordentlich, P.; Muscat, G. E. O. The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-Activation, Coactivator Recruitment, and Activation by the Purine Anti-Metabolite 6-Mercaptopurine. J. Biol. Chem. 2003, 278 (27), 24776– 24790, DOI: 10.1074/jbc.M300088200[Crossref], [PubMed], [CAS], Google Scholar366https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltVSlsrk%253D&md5=7e0a30de2f57a104fa8288fe90b485e9The AF-1 domain of the orphan nuclear receptor NOR-1 mediates trans-activation, coactivator recruitment, and activation by the purine anti-metabolite 6-mercaptopurineWansa, K. D. Senali Abayratna; Harris, Jonathan M.; Yan, Grace; Ordentlich, Peter; Muscat, George E. O.Journal of Biological Chemistry (2003), 278 (27), 24776-24790CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)NOR-1/NR4A3 is an "orphan member" of the nuclear hormone receptor superfamily. NOR-1 and its close relatives Nurr1 and Nur77 are members of the NR4A subgroup of nuclear receptors. Members of the NR4A subgroup are induced through multiple signal transduction pathways. They have been implicated in cell proliferation, differentiation, T-cell apoptosis, chondrosarcomas, neurol. disorders, inflammation, and atherogenesis. However, the mechanism of transcriptional activation, coactivator recruitment, and agonist-mediated activation remain obscure. Hence, we examd. the mol. basis of NOR-1-mediated activation. We obsd. that NOR-1 trans-activates gene expression in a cell- and target-specific manner; moreover, it operates in an activation function (AF)-1-dependent manner. The N-terminal AF-1 domain delimited to between amino acids 1 and 112, preferentially recruits the steroid receptor coactivator (SRC). Furthermore, SRC-2 modulates the activity of the AF-1 domain but not the C-terminal ligand binding domain (LBD). Homol. modeling indicated that the NOR-1 LBD was substantially different from that of hRORβ, a closely related AF-2-dependent receptor. In particular, the hydrophobic cleft characteristic of nuclear receptors was replaced with a very hydrophilic surface with a distinct topol. This observation may account for the inability of this nuclear receptor LBD to efficiently mediate cofactor recruitment and transcriptional activation. In contrast, the N-terminal AF-1 is necessary for cofactor recruitment and can independently conscript coactivators. Finally, we demonstrate that the purine anti-metabolite 6-mercaptopurine, a widely used antineoplastic and anti-inflammatory drug, activates NOR-1 in an AF-1-dependent manner. Addnl. 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity. We hypothesize that the NR4A subgroup mediates the genotoxic stress response and suggest that this subgroup may function as sensors that respond to genotoxicity.
- 363Yoo, Y. G.; Na, T. Y.; Yang, W. K.; Kim, H. J.; Lee, I. K.; Kong, G.; Chung, J. H.; Lee, M. O. 6-Mercaptopurine, an Activator of Nur77, Enhances Transcriptional Activity of HIF-1α Resulting in New Vessel Formation. Oncogene 2007, 26 (26), 3823– 3834, DOI: 10.1038/sj.onc.1210149[Crossref], [PubMed], [CAS], Google Scholar367https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlvFalu7Y%253D&md5=6dfa5569b47590e0086881347532c0106-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formationYoo, Y.-G.; Na, T.-Y.; Yang, W.-K.; Kim, H.-J.; Lee, I.-K.; Kong, G.; Chung, J.-H.; Lee, M.-O.Oncogene (2007), 26 (26), 3823-3834CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)Hypoxia-inducible factor-1α (HIF-1α) plays a central role in oxygen homeostasis. Previously, we reported that the orphan nuclear receptor Nur77 functions in stabilizing HIF-1α. Here, we demonstrate that 6-mercaptopurine (6-MP), an activator of the NR4A family members, enhances transcriptional activity of HIF-1. 6-MP enhanced the protein-level of HIF-1α as well as vascular endothelial growth factor (VEGF) in a dose- and time-dependent manner. The induction of HIF-1α was abolished by the transfection of either a dominant-neg. Nur77 mutant or si-Nur77, indicating a crit. role of Nur77 in the 6-MP action. The HIF-1α protein level remained up to 60 min in the presence of 6-MP when de novo protein synthesis was blocked by cycloheximide, suggesting that 6-MP induces stabilization of the HIF-1α protein. The fact that 6-MP decreased the assocn. of HIF-1α with von Hippel-Lindau protein and the acetylation of HIF-1α, may explain how 6-MP induced stability of HIF-1α. Further, 6-MP induced the transactivation function of HIF-1α by recruiting co-activator cyclic-AMP-response-element-binding protein. Finally, 6-MP enhanced the expression of HIF-1α and VEGF, and the formation of capillary tubes in human umbilical vascular endothelial cells. Together, our results provide a new insight for 6-MP action in the stabilization of HIF-1α and imply a potential application of 6-MP in hypoxia-assocd. human vascular diseases.
- 364Lee, H.-S.; Safe, S.; Lee, S.-O. Inactivation of the Orphan Nuclear Receptor NR4A1 Contributes to Apoptosis Induction by Fangchinoline in Pancreatic Cancer Cells. Toxicol. Appl. Pharmacol. 2017, 332, 32– 39, DOI: 10.1016/j.taap.2017.07.017[Crossref], [PubMed], [CAS], Google Scholar368https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1GitrvJ&md5=8362b6f90ea3e07cd74b9e092c142b9aInactivation of the orphan nuclear receptor nr4a1 contributes to apoptosis induction by fangchinoline in pancreatic cancer cellsLee, Hyo-Seon; Safe, Stephen; Lee, Syng-OokToxicology and Applied Pharmacology (2017), 332 (), 32-39CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)Previous studies have demonstrated that the orphan nuclear receptor NR4A1 is overexpressed in human pancreatic cancer and antagonizing this receptor promotes apoptosis and inhibits pancreatic cancer cells and tumor growth. In the present study, we identified fangchinoline, a bisbenzyltetrahydroisoquinoline alkaloid from Stephania tetrandra, as a new inactivator of nuclear NR4A1 and demonstrated that fangchinoline inhibits cell proliferation and induces apoptosis, in part, via the NR4A1-dependent pro-apoptotic pathways in human pancreatic cancer cells. It decreased expression of the antiapoptotic protein survivin by inhibiting Sp1-mediated transcription and induced oxidative stress-mediated endoplasmic reticulum (ER) stress in pancreatic cancer cells. These results suggest that inhibition of NR4A1-mediated transcriptional activity was involved in the anticancer effects of fangchinoline, and fangchinoline represents a novel class of mechanism-based anticancer agents targeting NR4A1 that is overexpressed in pancreatic cancer.
- 365Lee, S.-O.; Li, X.; Hedrick, E.; Jin, U.-H.; Tjalkens, R. B.; Backos, D. S.; Li, L.; Zhang, Y.; Wu, Q.; Safe, S. Diindolylmethane Analogs Bind NR4A1 and Are NR4A1 Antagonists in Colon Cancer Cells. Mol. Endocrinol. 2014, 28 (10), 1729– 1739, DOI: 10.1210/me.2014-1102[Crossref], [PubMed], [CAS], Google Scholar369https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslCns73K&md5=71c23c6b36e3b950d92f88c2d8d71068Diindolylmethane Analogs Bind Nr4a1 and Are Nr4a1 Antagonists In Colon Cancer CellsLee, Syng-Ook; Li, Xi; Hedrick, Erik; Jin, Un-Ho; Tjalkens, Ronald B.; Backos, Donald S.; Li, Li; Zhang, Yi; Wu, Qiao; Safe, StephenMolecular Endocrinology (2014), 28 (10), 1729-1739, 11 pp.CODEN: MOENEN; ISSN:1944-9917. (Endocrine Society)1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compds. exhibit antineoplastic activity in multiple cancer cell lines and the p-hydroxyphenyl analog (DIM-C-pPhOH) inactivates nuclear receptor 4A1 (NR4A1) in lung and pancreatic cancer cell lines. Using a series of 14 different p-substituted Ph C-DIMs, we show that several compds. including DIM-C-pPhOH directly interacted with the ligand binding domain of NR4A1. Computational-based mol. modeling studies showed high-affinity interactions of DIM-C-pPhOH and related compds. within the ligand binding pocket of NR4A1, and these same compds. decreased NR4A1-dependent transactivation in colon cancer cells transfected with a construct contg. 3 tandem Nur77 binding response elements linked to a luciferase reporter gene. Moreover, we also show that knockdown of NR4A1 by RNA interference (small interfering NR4A1) or treatment with DIM-C-pPhOH and related compds. decreased colon cancer cell growth, induced apoptosis, decreased expression of survivin and other Sp-regulated genes, and inhibited mammalian target of rapamycin signaling. Thus, C-DIMs such as DIM-C-pPhOH directly bind NR4A1 and are NR4A1 antagonists in colon cancer cells, and their antineoplastic activity is due, in part, to their interactions with nuclear NR4A1.
- 366Lee, S. O.; Abdelrahim, M.; Yoon, K.; Chintharlapalli, S.; Papineni, S.; Kim, K.; Wang, H.; Safe, S. Inactivation of the Orphan Nuclear Receptor TR3/Nur77 Inhibits Pancreatic Cancer Cell and Tumor Growth. Cancer Res. 2010, 70 (17), 6824– 6836, DOI: 10.1158/0008-5472.CAN-10-1992[Crossref], [PubMed], [CAS], Google Scholar370https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtV2rsLbF&md5=d32243cf686d3ac9ac80876ba3ac6a0cInactivation of the Orphan Nuclear Receptor TR3/Nur77 Inhibits Pancreatic Cancer Cell and Tumor GrowthLee, Syng-Ook; Abdelrahim, Maen; Yoon, Kyungsil; Chintharlapalli, Sudhakar; Papineni, Sabitha; Kim, Kyounghyun; Wang, Huamin; Safe, StephenCancer Research (2010), 70 (17), 6824-6836CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Activation of the orphan nuclear receptor TR3/Nur77 (NR4A1) promotes apoptosis and inhibits pancreatic tumor growth, but its endogenous function and the effects of its inactivation have yet to be detd. TR3 was overexpressed in human pancreatic tumors compared with nontumor tissue. Small interfering RNA-mediated knockdown of TR3 or cell treatment with the TR3 antagonist 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) decreased proliferation, induced apoptosis, and decreased expression of antiapoptotic genes including Bcl-2 and survivin in pancreatic cancer cells. Survivin suppression was mediated by formation of a TR3-Sp1-p300 DNA binding complex on the proximal GC-rich region of the survivin promoter. When administered in vivo, DIM-C-pPhOH induced apoptosis and inhibited tumor growth in an orthotopic model of pancreatic cancer, assocd. with inhibition of the same antiapoptotic markers obsd. in vitro. Our results offer preclin. validation of TR3 as a drug target for pancreatic cancer chemotherapy, based on the ability of TR3 inhibitors to block the growth of pancreatic tumors.
- 367Yoon, K.; Lee, S.-O.; Cho, S.-D.; Kim, K.; Khan, S.; Safe, S. Activation of Nuclear TR3 (NR4A1) by a Diindolylmethane Analog Induces Apoptosis and Proapoptotic Genes in Pancreatic Cancer Cells and Tumors. Carcinogenesis 2011, 32 (6), 836– 842, DOI: 10.1093/carcin/bgr040[Crossref], [PubMed], [CAS], Google Scholar371https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntFCksro%253D&md5=b93d269385bfc898334f2056cbcf46fdActivation of nuclear TR3 (NR4A1) by a diindolylmethane analog induces apoptosis and proapoptotic genes in pancreatic cancer cells and tumorsYoon, Kyung-Sil; Lee, Syng-Ook; Cho, Sung-Dae; Kim, Kyoung-Hyun; Khan, Sha-Heen; Safe, StephenCarcinogenesis (2011), 32 (6), 836-842CODEN: CRNGDP; ISSN:0143-3334. (Oxford University Press)NR4A1 (Nur77, TR3) is overexpressed in pancreatic tumors and activation of TR3 by 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (DIM-C-pPhOCH3) inhibits cell and tumor growth and induces apoptosis. Microarray anal. demonstrates that in L3.6pL pancreatic cancer cells DIM-C-pPhOCH3 induces genes assocd. with metab., homeostasis, signal transduction, transcription, stress, transport, immune responses, growth inhibition and apoptosis. Among the most highly induced growth inhibitory and proapoptotic genes including activating transcription factor 3 (ATF3), p21, cystathionase, dual specificity phosphatase 1 and growth differentiation factor 15, RNA interference studies demonstrated that induction of all but the later gene by DIM-C-pPhOCH3 were TR3-dependent. We also obsd. that DIM-C-pPhOCH3 induced Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and induction of TRAIL was ATF3 dependent. Results of this and previous studies demonstrate that TR3 is unique among nuclear receptors since nuclear TR3 is activated or deactivated by diindolylmethane derivs. to induce different apoptotic and growth inhibitory pathways that inhibit pancreatic cancer cell and tumor growth.
- 368Liu, J.; Wang, G.-H.; Duan, Y.-H.; Dai, Y.; Bao, Y.; Hu, M.; Zhou, Y.-Q.; Li, M.; Jiang, F.; Zhou, H.; Yao, X.-S.; Zhang, X.-K. Modulation of the Nur77-Bcl-2 Apoptotic Pathway by P38α MAPK. Oncotarget 2017, 8 (41), 69731– 69745, DOI: 10.18632/oncotarget.19227[Crossref], [PubMed], [CAS], Google Scholar372https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7isFWgug%253D%253D&md5=3325814a1b6136e56d94274201b0373aModulation of the Nur77-Bcl-2 apoptotic pathway by p38α MAPKLiu Jie; Wang Guang-Hui; Bao Yuzhou; Hu Mengjie; Zhou Yu-Qi; Li Mingyu; Jiang Fuquan; Zhou Hu; Zhang Xiao-Kun; Duan Ying-Hui; Dai Yi; Yao Xin-Sheng; Zhang Xiao-KunOncotarget (2017), 8 (41), 69731-69745 ISSN:.Orphan nuclear receptor Nur77 promotes apoptosis by targeting mitochondria through interaction with Bcl-2, an event that converts Bcl-2 from a survival to killer. However, how the Nur77-Bcl-2 apoptotic pathway is regulated remains largely unknown. In this study, we examined the regulation of the Nur77-Bcl-2 pathway by CCE9, a xanthone compound. Our results demonstrated that the apoptotic effect of CCE9 depended on its induction of Nur77 expression, cytoplasmic localization, and mitochondrial targeting. The activation of the Nur77-Bcl-2 pathway by CCE9 was associated with its activation of p38α MAPK. Inhibition of p38α MAPK activation by knocking down or knocking out p38α MAPK impaired the effect of CCE9 on inducing apoptosis and the expression and cytoplasmic localization of Nur77. In addition, CCE9 activation of p38α MAPK resulted in Bcl-2 phosphorylation and Bcl-2 interaction with Nur77, whereas inhibition of p38α MAPK activation or expression suppressed the interaction. Moreover, mutating Ser87 and Thr56 in the loop of Bcl-2, which are known to be phosphorylated by p38α MAPK, impaired the ability Bcl-2 to interact with Nur77. Together, our results reveal a profound role of p38α MAPK in regulating the Nur77-Bcl-2 apoptotic pathway through its modulation of Nur77 expression, Bcl-2 phosphorylation, and their interaction.
- 369Yao, L.-M.; He, J.-P.; Chen, H.-Z.; Wang, Y.; Wang, W.-J.; Wu, R.; Yu, C.-D.; Wu, Q. Orphan Receptor TR3 Participates in Cisplatin-Induced Apoptosis via Chk2 Phosphorylation to Repress Intestinal Tumorigenesis. Carcinogenesis 2012, 33 (2), 301– 311, DOI: 10.1093/carcin/bgr287[Crossref], [PubMed], [CAS], Google Scholar373https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVGisLk%253D&md5=9d6ce1a6cc34129c7c1a9800aff17e0cOrphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesisYao, Lu-ming; He, Jian-ping; Chen, Hang-zi; Wang, Yuan; Wang, Wei-jia; Wu, Rong; Yu, Chun-dong; Wu, QiaoCarcinogenesis (2012), 33 (2), 301-311CODEN: CRNGDP; ISSN:0143-3334. (Oxford University Press)Cisplatin is a widely used antitumor agent that induces aggressive cancer cell death via triggering cellular proteins involved in apoptosis. Here, we demonstrate that cisplatin effectively induces orphan nuclear receptor TR3 phosphorylation by activating Chk2 kinase activity and promoting cross talk between these 2 proteins, thereby contributing to the repression of intestinal tumorigenesis via apoptosis. Mechanistic anal. has demonstrated that Chk2-induced phosphorylation enables TR3 to bind to its response elements on the promoters of the BRE and RNF-7 genes, leading to the neg. regulation of these 2 anti-apoptotic genes. Furthermore, the induction of apoptosis by cisplatin is mediated by TR3, and knockdown of TR3 reduces cisplatin-induced apoptosis in colon cancer cells by 27%. The role of TR3 in cisplatin chemotherapy is further clarified in mouse models. In Apcmin/+ mice, cisplatin inhibits intestinal tumorigenesis by 70% in a TR3 phosphorylation-dependent manner; however, the loss of TR3 function in Apcmin/+/TR3-/- mice leads to the failure of cisplatin-induced repression of tumorigenesis. Consistently, xenografts derived from TR3 knockdown colon cancer cells are insensitive to cisplatin treatment, whereas a significant curative effect (50% inhibition) is obsd. in xenografts with functional TR3. Taken together, our study reveals a novel cross talk between Chk2 and TR3 and sheds light on the mechanism of cisplatin-induced apoptosis through TR3. Therefore, TR3 may be a new target of cisplatin for colon cancer therapy.
- 370Qi, H.; Jiang, Z.; Wang, C.; Yang, Y.; Li, L.; He, H.; Yu, Z. Sensitization of Tamoxifen-Resistant Breast Cancer Cells by Z-Ligustilide through Inhibiting Autophagy and Accumulating DNA Damages. Oncotarget 2017, 8 (17), 29300– 29317, DOI: 10.18632/oncotarget.16832[Crossref], [PubMed], [CAS], Google Scholar374https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1crgtVSrsw%253D%253D&md5=e58625798f05ea435727a8d80d699b93Sensitization of tamoxifen-resistant breast cancer cells by Z-ligustilide through inhibiting autophagy and accumulating DNA damagesQi Hongyi; Jiang Zhuyun; Wang Chengqiang; Yang Yi; Li Li; He Hui; Yu ZanyangOncotarget (2017), 8 (17), 29300-29317 ISSN:.Autophagy plays a pro-survival role in the tamoxifen-resistant breast cancer cells. Herein we found that autophagy was concomitantly induced in tamoxifen-resistant MCF-7 (MCF-7TR5) cells through the dissociation of Bcl-2 from Beclin 1 and subsequent enhancement of interaction among the ATG14-Beclin1-PI3KC3 complex. Moreover, higher level of DNA damage was observed in MCF-7TR5 cells with the decreased BRCA1 and RAD51 level and the increased Ku80 level. Interestingly, Nur77 was selectively degraded by autophagy, which causes the release of Ku80 from the Nur77-Ku80 complex, resulting in the increase of the DNA binding of Ku80 and DNA-PKcs. Meanwhile, Z-ligustilide, a phthalide compound from Radix Angelica sinensis, was shown to inhibit the autophagic flux by blocking the autophagosome-lysosome fusion. Importantly, Z-ligustilide-mediated autophagy inhibition restored Nur77 expression in MCF-7TR5 cells. Furthermore, Z-ligustilide promoted the interaction of Nur77 with Ku80 and thereby abolished the association of DNA-PKcs with DNA ends. Moreover, Z-ligustilide sensitized MCF-7TR5 cells in a caspase-independent cell death and enhanced the DNA damage caused by tamoxifen, which was found to be attenuated by shNur77. Together, these findings not only provide important insights into the formation of tamoxifen resistance in breast cancer cells, but also suggest Z-ligustilide may function as a novel autophagy inhibitor to overcome chemoresistance.
- 371Codina, A.; Benoit, G.; Gooch, J. T.; Neuhaus, D.; Perlmann, T.; Schwabe, J. W. R. Identification of a Novel Co-Regulator Interaction Surface on the Ligand Binding Domain of Nurr1 Using NMR Footprinting. J. Biol. Chem. 2004, 279 (51), 53338– 53345, DOI: 10.1074/jbc.M409096200[Crossref], [PubMed], [CAS], Google Scholar375https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVKqurfJ&md5=834e486a607271be30ace435e62ccb5fIdentification of a Novel Co-regulator Interaction Surface on the Ligand Binding Domain of Nurr1 Using NMR FootprintingCodina, Anna; Benoit, Gerard; Gooch, John T.; Neuhaus, David; Perlmann, Thomas; Schwabe, John W. R.Journal of Biological Chemistry (2004), 279 (51), 53338-53345CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The nuclear receptor Nurr1 is a transcription factor essential for the development of midbrain dopaminergic neurons in vertebrates. Recent crystal structures of the Nurr1 ligand binding domain (LBD) and the Drosophila orthologue dHR38 revealed that, although these receptors share the classical LBD architecture, they lack a ligand binding cavity. This vol. is instead filled with bulky hydrophobic side chains. Furthermore the "canonical" non-polar co-regulator binding groove is filled with polar side chains; thus, the regulation of transcription by this sub-family of nuclear receptor LBDs may be mediated by some other interaction surface on the LBD. We report here the identification of a novel co-regulator interface on the LBD of Nurr1. We used an NMR footprinting strategy that facilitates the identification of an interaction surface without the need of a full assignment. We found that non-polar peptides derived from the co-repressors SMRT and NCoR bind to a hydrophobic patch on the LBD of Nurr1. This binding surface involves a groove between helixes 11 and 12. Mutations in this site abolish activation by the Nurr1 LBD. These findings give insight into the unique mechanism of action of this class of nuclear receptors.
- 372Volakakis, N.; Malewicz, M.; Kadkhodai, B.; Perlmann, T.; Benoit, G. Characterization of the Nurr1 Ligand-Binding Domin Co-Activator Interaction Surface. J. Mol. Endocrinol. 2006, 37 (2), 317– 326, DOI: 10.1677/jme.1.02106[Crossref], [PubMed], [CAS], Google Scholar376https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1eju7vK&md5=edf8570136cd3cc79d05db7f4114d95eCharacterization of the Nurr1 ligand-binding domain co-activator interaction surfaceVolakakis, Nikolaos; Malewicz, Michal; Kadkhodai, Banafsheh; Perlmann, Thomas; Benoit, GerardJournal of Molecular Endocrinology (2006), 37 (2), 317-326CODEN: JMLEEI; ISSN:0952-5041. (Society for Endocrinology)The recently solved crystal structure of the orphan nuclear receptor (NR) Nurr1 ligand-binding domain (LBD) showed that Nurr1 lacks a cavity for ligand binding and a canonical NR co-activator-binding site. Computer modeling of the Nurr1 LBD structure identified a hydrophobic region on the surface of the Nurr1 LBD that was positioned on the opposite side from the classical co-activator-binding site. Site-directed mutagenesis demonstrated that this region is crit. for the activity of the Nurr1 LBD. Most mutations introduced in this region reduced or abolished transcriptional activity of the Nurr1 LBD, but mutation at lysine (K577) resulted in a drastically increased activity. Moreover, the activity of the Nurr1 LBD was shown to correlate with a propensity for proteasome-dependent degrdn. revealing a close assocn. between activity and Nurr1 protein turnover. These data provide novel insights into the mechanisms of transcription via the Nurr1 LBD and identify an alternative co-activator-binding surface that is unique to the NR4A family of NRs.
- 373Galleguillos, D.; Vecchiola, A.; Fuentealba, J. A.; Ojeda, V.; Alvarez, K.; Gómez, A.; Andrés, M. E. PIASγ Represses the Transcriptional Activation Induced by the Nuclear Receptor Nurr1. J. Biol. Chem. 2004, 279 (3), 2005– 2011, DOI: 10.1074/jbc.M308113200[Crossref], [PubMed], [CAS], Google Scholar377https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisF2qtQ%253D%253D&md5=154c65f97c2dc753bff88f5f35c74c00PIASγ represses the transcriptional activation induced by the nuclear receptor Nurr1Galleguillos, Danny; Vecchiola, Andrea; Fuentealba, Jose Antonio; Ojeda, Viviana; Alvarez, Karin; Gomez, Andrea; Andres, Maria EstelaJournal of Biological Chemistry (2004), 279 (3), 2005-2011CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Nurr1 is a transcription factor essential for the development of ventral dopaminergic neurons. In search for regulatory mechanisms of Nurr1 function, we identified the SUMO (small ubiquitin-like modifier)-E3 ubiquitin-protein isopeptide ligase, PIASγ, as an interaction partner of Nurr1. Overexpressed PIASγ and Nurr1 co-localize in the nuclei of transfected cells, and their interaction is demonstrated through co-immunopptn. and glutathione S-transferase pulldown assays. Co-expression of PIASγ with Nurr1 results in a potent repression of Nurr1-dependent transcriptional activation of an artificial NGFI-B response element (NBRE) reporter as well as of a reporter driven by the native tyrosine hydroxylase promoter. We identified two consensus sumoylation sites in Nurr1. The substitution of lysine 91 by arginine in one SUMO site enhanced the transcriptional activity of Nurr1, whereas the substitution of lysine 577 by arginine in the second SUMO site decreased transcriptional activity of Nurr1. Interestingly, PIASγ-induced repression of Nurr1 activity does not require the two sumoylation sites, because each mutant is repressed as efficiently as the wild type Nurr1. In addn., the mutations do not alter Nurr1 nuclear localization. Finally, we provide evidence that Nurr1 and PIASγ co-exist in several nuclei of the rodent central nervous system by demonstrating the co-expression of Nurr1 protein and PIASγ mRNA in the same cells. In conclusion, our studies identified PIASγ as a transcriptional co-regulator of Nurr1 and suggest that this interaction may have a physiol. role in regulating the expression of Nurr1 target genes.
- 374Zetterström, R. H.; Solomin, L.; Jansson, L.; Hoffer, B. J.; Olson, L.; Perlmann, T. Dopamine Neuron Agenesis in Nurr1-Deficient Mice. Science 1997, 276 (5310), 248– 250, DOI: 10.1126/science.276.5310.248[Crossref], [PubMed], [CAS], Google Scholar378https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3kvVKgtw%253D%253D&md5=d43da1dfc9d7266ff0c6ad72c453c8a1Dopamine neuron agenesis in Nurr1-deficient miceZetterstrom R H; Solomin L; Jansson L; Hoffer B J; Olson L; Perlmann TScience (New York, N.Y.) (1997), 276 (5310), 248-50 ISSN:0036-8075.Dopamine neurons of the substantia nigra and ventral tegmental area regulate movement and affective behavior and degenerate in Parkinson's disease. The orphan nuclear receptor Nurr1 was shown to be expressed in developing dopamine neurons before the appearance of known phenotypic markers for these cells. Mice lacking Nurr1 failed to generate midbrain dopaminergic neurons, were hypoactive, and died soon after birth. Nurr1 expression continued into adulthood, and brains of heterozygous animals, otherwise apparently healthy, contained reduced dopamine levels. These results suggest that putative Nurr1 ligands may be useful for treatment of Parkinson's disease and other disorders of midbrain dopamine circuitry.
- 375Wallén, Å.; Zetterström, R. H.; Solomin, L.; Arvidsson, M.; Olson, L.; Perlmann, T. Fate of Mesencephalic AHD2-Expressing Dopamine Progenitor Cells in Nurr1Mutant Mice. Exp. Cell Res. 1999, 253 (2), 737– 746, DOI: 10.1006/excr.1999.4691[Crossref], [PubMed], [CAS], Google Scholar379https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXns1ams7s%253D&md5=a7c93f4ac4dc7ff067dda4b0a81c6e49Fate of Mesencephalic AHD2-Expressing Dopamine Progenitor Cells in Nurr1 Mutant MiceWallen, Aasa; Zetterstrom, Rolf H.; Solomin, Ludmila; Arvidsson, Mariette; Olson, Lars; Perlmann, ThomasExperimental Cell Research (1999), 253 (2), 737-746CODEN: ECREAL; ISSN:0014-4827. (Academic Press)The orphan nuclear receptor NURR1 was previously demonstrated to be required for the generation of mesencephalic dopamine (DA) cells. However, even in the absence of NURR1, which is normally expressed as cells become postmitotic, neuronal differentiation is induced and expression of several genes detected in developing dopamine cells appears normal during early stages of development. These include the homeobox transcription factors engrailed and Ptx-3 as well as aldehyde dehydrogenase 2, here defined as the earliest marker identified in developing DA cells, expressed already in mitotic DA progenitors. The authors have used the expression of these dopaminergic markers, retrograde axonal tracing, and apoptosis analyses to study the fate of the DA progenitor cells in the absence of NURR1. The authors conclude that NURR1 plays a crit. role in the maturation, migration, striatal target area innervation, and survival of differentiating mesencephalic DA cells. (c) 1999 Academic Press.
- 376Smits, S. M.; Ponnio, T.; Conneely, O. M.; Burbach, J. P. H.; Smidt, M. P. Involvement of Nurr1 in Specifying the Neurotransmitter Identity of Ventral Midbrain Dopaminergic Neurons. Eur. J. Neurosci. 2003, 18 (7), 1731– 1738, DOI: 10.1046/j.1460-9568.2003.02885.x[Crossref], [PubMed], [CAS], Google Scholar380https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3srks12ntQ%253D%253D&md5=fe0562191d66ada0636016078fcd1611Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neuronsSmits Simone M; Ponnio Tiia; Conneely Orla M; Burbach J Peter H; Smidt Marten PThe European journal of neuroscience (2003), 18 (7), 1731-8 ISSN:0953-816X.The mesencephalic dopaminergic (mesDA) system is involved in many brain functions including motor control and motivated behaviour, and is of clinical importance because of its implication in psychiatric disorders and Parkinson's disease. Nurr1, a member of the nuclear hormone receptor superfamily of transcription factors, is essential for establishing the dopaminergic phenotype, because expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, requires Nurr1. In addition, Nurr1 plays an important role in the maintenance of mesDA neurons. Neonatal Nurr1 knockout mice lack expression of the dopamine transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and l-aromatic amino acid decarboxylase (AADC) in addition to TH specifically in mesDA neurons. It is unclear whether the lack of expression of these dopaminergic markers is caused by a maintenance defect or whether the induction of these markers depends on Nurr1 expression. To address this problem, the expression of DAT, VMAT2 and AADC was analysed at embryonic day 12.5 and 14.5. Here we demonstrate that induction of VMAT2 and DAT specifically in mesDA neurons requires Nurr1 expression, whereas AADC expression in mesDA neurons is induced independently of Nurr1 function.
- 377Hermanson, E.; Joseph, B.; Castro, D.; Lindqvist, E.; Aarnisalo, P.; Wallén, Å.; Benoit, G.; Hengerer, B.; Olson, L.; Perlmann, T. Nurr1 Regulates Dopamine Synthesis and Storage in MN9D Dopamine Cells. Exp. Cell Res. 2003, 288 (2), 324– 334, DOI: 10.1016/S0014-4827(03)00216-7[Crossref], [PubMed], [CAS], Google Scholar381https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmt1ehurg%253D&md5=21af82cbad4208df496aa2044cf8c510Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cellsHermanson, Elisabet; Joseph, Bertrand; Castro, Diogo; Lindqvist, Eva; Aarnisalo, Piia; Wallen, Asa; Benoit, Gerard; Hengerer, Bastian; Olson, Lars; Perlmann, ThomasExperimental Cell Research (2003), 288 (2), 324-334CODEN: ECREAL; ISSN:0014-4827. (Elsevier Science)Nurr1, a transcription factor belonging to the nuclear receptor family, is essential for the generation of midbrain dopamine (DA) cells during embryonic development. Nurr1 continues to be expressed in adult DA neurons but the role for Nurr1 in inducing and regulating basic dopaminergic functions such as dopamine synthesis and storage has remained unknown. The authors have previously used MN9D dopamine cells to analyze the role of Nurr1 and retinoids in DA cell maturation. These studies demonstrated that both Nurr1 and retinoids induce cell cycle arrest and a mature morphol. Here the authors used MN9D cells to investigate how Nurr1 regulates dopaminergic functions. The authors' results demonstrate that Nurr1, but not retinoids, increases DA content and the expression of arom. L-amino acid decarboxylase (AADC) and vesicular monoamine transporter-2 (VMAT2) in MN9D cells. In a Nurr1-inducible cell line upregulation of VMAT2 is dependent on continuous Nurr1 expression. Moreover, AADC and VMAT2 are deregulated in midbrain DA cells of Nurr1 knockout embryos as revealed by in situ hybridization. Together, the results provide evidence indicating an instructive role for Nurr1 in controlling DA synthesis and storage.
- 378Jacobs, F. M. J.; van der Linden, A. J. A.; Wang, Y.; von Oerthel, L.; Sul, H. S.; Burbach, J. P. H.; Smidt, M. P. Identification of Dlk1, Ptpru and Klhl1 as Novel Nurr1 Target Genes in Meso-Diencephalic Dopamine Neurons. Development 2009, 136 (14), 2363– 2373, DOI: 10.1242/dev.037556[Crossref], [PubMed], [CAS], Google Scholar382https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpvFGgtbw%253D&md5=5670ef9db289ea3357c06fc3cb9f8c39Identification of Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in meso-diencephalic dopamine neuronsJacobs, Frank M. J.; van der Linden, Annemarie J. A.; Wang, Yuhui; von Oerthel, Lars; Sul, Hei Sook; Burbach, J. Peter H.; Smidt, Marten P.Development (Cambridge, United Kingdom) (2009), 136 (14), 2363-2373CODEN: DEVPED; ISSN:0950-1991. (Company of Biologists Ltd.)The orphan nuclear receptor Nurr1 is essential for the development of meso-diencephalic dopamine (mdDA) neurons and is required, together with the homeobox transcription factor Pitx3, for the expression of genes involved in dopamine metab. To elucidate the mol. mechanisms that underlie the neuronal deficits in Nurr1-/- mice, the authors performed combined gene expression microarrays and ChIP-on-chip anal. and thereby identified Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in vivo. In line with the previously described cooperativity between Nurr1 and Pitx3, the authors show that the expression of Ptpru and Klhl1 in mdDA neurons is also dependent on Pitx3. Furthermore, the authors demonstrate that Nurr1 interacts with the Ptpru promoter directly and requires Pitx3 for full expression of Ptpru in mdDA neurons. By contrast, the expression of Dlk1 is maintained in Pitx3-/- embryos and is even expanded into the rostral part of the mdDA area, suggesting a unique position of Dlk1 in the Nurr1 and Pitx3 transcriptional cascades. Expression anal. in Dlk1-/- embryos reveals that Dlk1 is required to prevent premature expression of Dat in mdDA neuronal precursors as part of the multifaceted process of mdDA neuronal differentiation driven by Nurr1 and Pitx3. Taken together, the involvement of Nurr1 and Pitx3 in the expression of novel target genes involved in important neuronal processes such as neuronal patterning, axon outgrowth and terminal differentiation, opens up new avenues to study the properties of mdDA neurons during development and in neuronal pathol. as obsd. in Parkinson's disease.
- 379Gil, M.; McKinney, C.; Lee, M. K.; Eells, J. B.; Phyillaier, M. A.; Nikodem, V. M. Regulation of GTP Cyclohydrolase I Expression by Orphan Receptor Nurr1 in Cell Culture and in Vivo. J. Neurochem. 2007, 101 (1), 142– 150, DOI: 10.1111/j.1471-4159.2006.04356.x[Crossref], [PubMed], [CAS], Google Scholar383https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXksFSqsbs%253D&md5=fd52963bb097c5a8fead9538497f3743Regulation of GTP cyclohydrolase I expression by orphan receptor Nurr1 in cell culture and in vivoGil, Minchan; McKinney, Cushla; Lee, Mi Kyeong; Eells, Jeffrey B.; Phyillaier, Marcia A.; Nikodem, Vera M.Journal of Neurochemistry (2007), 101 (1), 142-150CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)Nurr1 is an orphan nuclear transcription factor essential for the terminal differentiation of dopamine (DA) neurons in the ventral midbrain (VM). To identify the Nurr1-target genes, we carried out microarray and quant. real-time PCR analyses of Nurr1 null and wild-type mice in VM at embryonic day (E) 12.5 and shortly after birth (P0). In addn. to the absence of mRNAs of DA synthesizing enzymes, the GTP (GTP) cyclohydrolase I (GTPCH) was also substantially reduced in the VM of Nurr1-null mice. GTPCH is the first enzyme in the synthesis pathway of tetrahydrobiopterin (BH4), an essential cofactor for tyrosine hydroxylase in DA synthesis. In the mouse, Nurr1 and GTPCH mRNA were first detected at E10.5, and GTPCH transcription paralleled that of Nurr1. Small interfering RNA targeted against Nurr1 decreases GTPCH expression in MC3T3-E1 osteoblasts in cell culture. Cotransfection of Nurr1 and the GTPCH-luciferase (luc) reporter increased the luc activity by about threefold in N2A cells. Addnl. anal. using 5'-deletions and mutants revealed that Nurr1 activates GTPCH transcription indirectly through the proximal promoter region, in the absence of the nerve growth factor-induced clone B (NGFI-B) responsive element-like sites, similarly, as recently reported for DA transporter regulation by Nurr1.
- 380Luo, Y.; Henricksen, L. A.; Giuliano, R. E.; Prifti, L.; Callahan, L. M.; Federoff, H. J. VIP Is a Transcriptional Target of Nurr1 in Dopaminergic Cells. Exp. Neurol. 2007, 203 (1), 221– 232, DOI: 10.1016/j.expneurol.2006.08.005[Crossref], [PubMed], [CAS], Google Scholar384https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1Krt73O&md5=2f4c1bf011cc81bb73c3e7e601c9d1b5VIP is a transcriptional target of Nurr1 in dopaminergic cellsLuo, Yu; Henricksen, Leigh A.; Giuliano, Rita E.; Prifti, Llanda; Callahan, Linda M.; Federoff, Howard J.Experimental Neurology (2007), 203 (1), 221-232CODEN: EXNEAC; ISSN:0014-4886. (Elsevier)The orphan nuclear receptor Nurr1 is required for the development of the ventral mesencephalic dopaminergic neurons. These are the same neurons that are invariantly lost in patients with Parkinson's disease. Nurr1 mRNA expression is not confined to the developing midbrain, and yet Nurr1 appears to be essential for either the maturation of progenitors into fully post-mitotic dopaminergic neurons and/or once formed, their survival. The function of Nurr1 in the transactivation of gene(s) important for neuronal development and/or maintenance is uncharacterized. To characterize potential downstream target genes of Nurr1, we sought to identify mRNAs that are differentially affected by Nurr1 expression. Using a dopaminergic cell line in which Nurr1 content was tightly regulated, differential display anal. identified transcripts altered by Nurr1 expression, including the mRNA encoding vasoactive intestinal peptide (VIP). Herein, we demonstrate that Nurr1 regulates VIP mRNA and protein levels, and transactivates the VIP promoter through Nurr1-responsive cis elements. In addn., dopaminergic cells release and utilize VIP to mediate survival when challenged with paraquat. Nurr1 regulation of VIP is also demonstrated in vivo as loss of Nurr1 function results in diminished VIP mRNA levels within the developing midbrain.
- 381Wallén, Å.; Castro, D. S.; Zetterström, R. H.; Karlén, M.; Olson, L.; Ericson, J.; Perlmann, T. Orphan Nuclear Receptor Nurr1 Is Essential for Ret Expression in Midbrain Dopamine Neurons and in the Brain Stem. Mol. Cell. Neurosci. 2001, 18 (6), 649– 663, DOI: 10.1006/mcne.2001.1057[Crossref], [PubMed], [CAS], Google Scholar385https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXptFegtbc%253D&md5=c1a76324ad2202dcf2cba48ff75e0ea4Orphan Nuclear Receptor Nurr1 Is Essential for Ret Expression in Midbrain Dopamine Neurons and in the Brain StemWallen, Asa; Castro, Diogo S.; Zetterstroem, Rolf H.; Karlen, Mattias; Olson, Lars; Ericson, Johan; Perlmann, ThomasMolecular and Cellular Neuroscience (2001), 18 (6), 649-663CODEN: MOCNED; ISSN:1044-7431. (Academic Press)The orphan nuclear receptor Nurr1 is essential for development of midbrain dopamine (DA) cells. In Nurr1-deficient mice, DA precursor cells fail to migrate normally, are unable to innervate target areas, and only transiently express DA cell marker genes. In the search for Nurr1-regulated genes that might explain this developmental phenotype, the authors found that expression of the receptor tyrosine kinase Ret is deregulated in these cells of Nurr1-deficient embryos. In addn., the authors' analyses establish Nurr1 as an early marker for the dorsal motor nucleus (DMN) of the vagus nerve. Interestingly, Ret expression is absent also in these cells in Nurr1-targeted mice. Neuronal innervation of vagus nerve target areas appeared normal apart from a subtle disorganization of the DMN-derived nerve fibers. In conclusion, regulation of Ret by Nurr1 in midbrain DA neurons and in the DMN has implications for both embryonal development and adult physiol. in which signaling by neurotrophic factors plays important roles. (c) 2001 Academic Press.
- 382Heng, X.; Jin, G.; Zhang, X.; Yang, D.; Zhu, M.; Fu, S.; Li, X.; Le, W. Nurr1 Regulates Top IIβ and Functions in Axon Genesis of Mesencephalic Dopaminergic Neurons. Mol. Neurodegener. 2012, 7 (1), 4, DOI: 10.1186/1750-1326-7-4[Crossref], [PubMed], [CAS], Google Scholar386https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotFKqtLc%253D&md5=04ed715adc18a156f0b28a887f8ab862Nurr1 regulates Top IIβ and functions in axon genesis of mesencephalic dopaminergic neuronsHeng, Xin; Jin, Gang; Zhang, Xin; Yang, Dehuang; Zhu, Mingzhe; Fu, Shijun; Li, Xuping; Le, WeidongMolecular Neurodegeneration (2012), 7 (), 4CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)Background: NURR1 (also named as NR4A2) is a member of the steroid/thyroid hormone receptor family, which can bind to DNA and modulate expression of target genes. Previous studies have shown that NURR1 is essential for the nigral dopaminergic neuron phenotype and function maintenance and the defects of the gene are possibly assocd. with Parkinson's disease (PD). Results: In this study, we used new born Nurr1 knock-out mice combined with Affymetrix genechip technol. and real time polymerase chain reaction (PCR) to identify Nurr1 regulated genes, which led to the discovery of several transcripts differentially expressed in the nigro-striatal pathway of Nurr1 knock-out mice. We found that an axon genesis gene called Topoisomerase IIβ (Top IIβ) was down-regulated in Nurr1 knock-out mice and we identified two functional NURR1 binding sites in the proximal Top IIβ promoter. While in Top IIβ null mice, we saw a significant loss of dopaminergic neurons in the substantial nigra and lack of neurites along the nigro-striatal pathway. Using specific TOP II antagonist ICRF-193 or Top IIβ siRNA in the primary cultures of ventral mesencephalic (VM) neurons, we documented that suppression of TOP IIβ expression resulted in VM neurites shortening and growth cones collapsing. Furthermore, microinjection of ICRF-193 into the mouse medial forebrain bundle (MFB) led to the loss of nigro-striatal projection. Conclusion: Taken together, our findings suggest that Top IIβ might be a down-stream target of Nurr1, which might influence the processes of axon genesis in dopaminergic neurons via the regulation of TOP IIβ expression. The Nurr1-Top IIβ interaction may shed light on the pathol. role of Nurr1 defect in the nigro-striatal pathway deficiency assocd. with PD.
- 383Montarolo, F.; Martire, S.; Perga, S.; Spadaro, M.; Brescia, I.; Allegra, S.; De Francia, S.; Bertolotto, A. NURR1 Deficiency Is Associated to ADHD-like Phenotypes in Mice. Transl. Psychiatry 2019, 9 (1), 207, DOI: 10.1038/s41398-019-0544-0[Crossref], [PubMed], [CAS], Google Scholar387https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3Mrit1KhsQ%253D%253D&md5=90bfd9ffda4c02f020121bd232b1d303NURR1 deficiency is associated to ADHD-like phenotypes in miceMontarolo Francesca; Martire Serena; Perga Simona; Spadaro Michela; Bertolotto Antonio; Montarolo Francesca; Martire Serena; Perga Simona; Spadaro Michela; Bertolotto Antonio; Montarolo Francesca; Perga Simona; Brescia Irene; Allegra Sarah; De Francia SilviaTranslational psychiatry (2019), 9 (1), 207 ISSN:.The transcription factor NURR1 regulates the dopamine (DA) signaling pathway and exerts a critical role in the development of midbrain dopaminergic neurons (mDA). NURR1 alterations have been linked to DA-associated brain disorders, such as Parkinson's disease and schizophrenia. However, the association between NURR1 defects and the attention-deficit hyperactivity disorder (ADHD), a DA-associated brain disease characterized by hyperactivity, impulsivity and inattention, has never been demonstrated. To date, a comprehensive murine model of ADHD truly reflecting the whole complex human psychiatric disorder still does not exist. NURR1-knockout (NURR1-KO) mice have been reported to exhibit increased spontaneous locomotor activity, but their complete characterization is still lacking. In the present study a wide-ranging test battery was used to perform a comprehensive analysis of the behavioral phenotype of the male NURR1-KO mice. As a result, their hyperactive phenotype was confirmed, while their impulsive behavior was reported for the first time. On the other hand, no anxiety and alterations in motor coordination, sociability and memory were observed. Also, the number of mDA expressing tyrosine hydroxylase, a rate-limiting enzyme of catecholamines biosynthesis, and DA level in brain were not impaired in NURR1-KO mice. Finally, hyperactivity has been shown to be recovered by treatment with methylphenidate, the first line psychostimulant drug used for ADHD. Overall, our study suggests that the NURR1 deficient male mouse may be a satisfactory model to study some ADHD behavioral phenotypes and to test the clinical efficacy of potential therapeutic agents.
- 384McCoy, J. M.; Walkenhorst, D. E.; McCauley, K. S.; Elaasar, H.; Everett, J. R.; Mix, K. S. Orphan Nuclear Receptor NR4A2 Induces Transcription of the Immunomodulatory Peptide Hormone Prolactin. J. Inflammation 2015, 12, 13, DOI: 10.1186/s12950-015-0059-2[Crossref], [CAS], Google Scholar388https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MrptVOitA%253D%253D&md5=5418e7c9413369471ffa90d4bee47bb6Orphan nuclear receptor NR4A2 induces transcription of the immunomodulatory peptide hormone prolactinMcCoy Joseph M; Walkenhorst Dana E; McCauley Keegan S; Elaasar Hiba; Everett Jordan R; Mix Kimberlee SJournal of inflammation (London, England) (2015), 12 (), 13 ISSN:1476-9255.BACKGROUND: Nuclear receptor 4A2 (NR4A2) is an orphan nuclear receptor and constitutively active transcription factor expressed at elevated levels in inflamed joint tissues from patients with arthritis. Inflammatory mediators rapidly and potently induce NR4A2 expression in resident joint cells and infiltrating immune cells. This receptor promotes synovial hyperplasia by increasing proliferation of synoviocytes and inducing transcription of matrix degrading enzymes and pro-inflammatory mediators. In order to further elucidate the molecular mechanisms of NR4A2, we conducted a gene expression screen to identify novel transcriptional targets of NR4A2 that may contribute to arthritis progression. METHODS: NR4A2 was over-expressed in human synoviocytes by lentiviral transduction and gene expression changes were measured using qPCR arrays specific for inflammation, proliferation, adhesion, and migration pathways. Subsequent analysis focused on the most potently induced gene prolactin (PRL). Messenger RNA levels of PRL and PRL receptor (PRL-R) were measured by RT-qPCR and protein levels were measured by ELISA. PRL promoter studies were conducted in synoviocytes transiently transfected with NR4A2 and PRL reporter constructs. Molecular responses to PRL in synoviocytes were addressed using qPCR arrays specific for JAK/STAT signaling pathways. RESULTS: PRL was the most potently induced gene on the qPCR arrays, exhibiting a 68-fold increase in response to ectopic NR4A2. This gene encodes an immunomodulatory peptide hormone with roles in autoimmune diseases and inflammation. Induction of PRL mRNA and secreted protein by NR4A2 was confirmed in subsequent experiments, with increases of 300-fold and 18-fold respectively. Depletion of endogenous NR4A receptors with shRNA reduced basal and PGE2-induced PRL levels by 95%. At the transcriptional level, NR4A2 requires a functional DNA binding domain to transactivate the distal PRL promoter. Deletional analysis indicates that NR4A2 targets a region of the distal PRL promoter spanning -270 to -32 bp. In synoviocytes, recombinant PRL regulates several genes involved in inflammation, proliferation, and cell survival, suggesting that NR4A2 induced PRL may also impact these pathways and contribute to arthritis progression. CONCLUSIONS: These results provide the first evidence for transcriptional regulation of the immunomodulatory peptide hormone PRL by NR4A2 in synoviocytes, and highlight a novel molecular pathway in inflammatory arthritis.
- 385Safe, S.; Jin, U. H.; Morpurgo, B.; Abudayyeh, A.; Singh, M.; Tjalkens, R. B. Nuclear Receptor 4A (NR4A) Family - Orphans No More. J. Steroid Biochem. Mol. Biol. 2016, 157, 48– 60, DOI: 10.1016/j.jsbmb.2015.04.016[Crossref], [PubMed], [CAS], Google Scholar389https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnt1Wjs7k%253D&md5=1dbc9721e70c9f19ea72032a60d351feNuclear receptor 4A (NR4A) family - orphans no moreSafe, Stephen; Jin, Un-Ho; Morpurgo, Benjamin; Abudayyeh, Ala; Singh, Mandip; Tjalkens, Ronald B.Journal of Steroid Biochemistry and Molecular Biology (2016), 157 (), 48-60CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)The orphan nuclear receptors NR4A1, NR4A2 and NR4A3 are immediate early genes induced by multiple stressors, and the NR4A receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurol. functions and also in inflammation and inflammatory diseases and in immune functions and cancer. Despite the similarities of NR4A1, NR4A2 and NR4A3 and their interactions with common cis-genomic elements, they exhibit unique activities and cell-/tissue-specific functions. Although endogenous ligands for NR4A receptors have not been identified, there is increasing evidence that structurally-diverse synthetic mols. can directly interact with the ligand binding domain of NR4A1 and act as agonists or antagonists, and ligands for NR4A2 and NR4A3 have also been identified. Since NR4A receptors are key factors in multiple diseases, there are opportunities for the future development of NR4A ligands for clin. applications in treating multiple health problems including metabolic, neurol. and cardiovascular diseases, other inflammatory conditions, and cancer.
- 386Decressac, M.; Volakakis, N.; Björklund, A.; Perlmann, T. NURR1 in Parkinson Disease - From Pathogenesis to Therapeutic Potential. Nat. Rev. Neurol. 2013, 9 (11), 629– 636, DOI: 10.1038/nrneurol.2013.209[Crossref], [PubMed], [CAS], Google Scholar390https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1ChsrjJ&md5=0ccc0530d53c1d19ef38e81307b99691NURR1 in Parkinson disease-from pathogenesis to therapeutic potentialDecressac, Mickael; Volakakis, Nikolaos; Bjoerklund, Anders; Perlmann, ThomasNature Reviews Neurology (2013), 9 (11), 629-636CODEN: NRNACP; ISSN:1759-4758. (Nature Publishing Group)A review. In Parkinson disease (PD), affected midbrain dopamine (DA) neurons lose specific dopaminergic properties before the neurons die. How the phenotype of DA neurons is normally established and the ways in which pathol. affects the maintenance of cell identity are, therefore, important considerations. Orphan nuclear receptor NURR1 (NURR1, also known as NR4A2) is involved in the differentiation of midbrain DA neurons, but also has an important role in the adult brain. Emerging evidence indicates that impaired NURR1 function might contribute to the pathogenesis of PD: NURR1 and its transcriptional targets are downregulated in midbrain DA neurons that express high levels of the disease-causing protein α-synuclein. Clin. and exptl. data indicate that disrupted NURR1 function contributes to induction of DA neuron dysfunction, which is seen in early stages of PD. The likely involvement of NURR1 in the development and progression of PD makes this protein a potentially interesting target for therapeutic intervention.
- 387Liu, H.; Liu, H.; Li, T.; Cui, J.; Fu, Y.; Ren, J.; Sun, X.; Jiang, P.; Yu, S.; Li, C. NR4A2 Genetic Variation and Parkinson’s Disease: Evidence from a Systematic Review and Meta-Analysis. Neurosci. Lett. 2017, 650, 25– 32, DOI: 10.1016/j.neulet.2017.01.062[Crossref], [PubMed], [CAS], Google Scholar391https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmtVymsLo%253D&md5=bf8113ddd6ffc1cd79ee68fcdca001baNR4A2 genetic variation and Parkinson's disease: Evidence from a systematic review and meta-analysisLiu, Hongmei; Liu, Hongbo; Li, Ting; Cui, Jiayi; Fu, Yingmei; Ren, Juanjuan; Sun, Xiujia; Jiang, Ping; Yu, Shunying; Li, ChunboNeuroscience Letters (2017), 650 (), 25-32CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)The homo sapiens nuclear receptor subfamily 4, group A (NR4A2) genetic variation has been implicated as a risk factor for Parkinson's disease (PD). Nevertheless, the results are inconclusive. We conducted a comprehensive systematic review and meta-anal. to quantify the impact of NR4A2 variation on the risk of PD.all eligible case-control studies published up to June 2016 by searching Pubmed, OVID, EBSCO, PsycINFO, ISI Web of Knowledge, Chinese Biomedical Literature Database and China Academic Journals Database were identified. Pooled odds ratio (OR) with 95% confidence interval (CI) were used to access the strength of the assocn. in fixed- or random-effects model.eighteen studies reported 24 genetic variants with a total of 6150 cases and 5919 controls were included. Twelve studies for NR4A2 rs35479735 polymorphism and 4 studies for rs12803 were available for meta-anal. A significant assocn. was obsd. for rs35479735 under the homozygous model (OR = 1.31, 95% CI: 1.10-1.56, P = 0.003), whereas no significant assocn. for rs12803 was detected. In subgroup anal. stratified by ethnicity, age onset and familial history, we found no significant assocn. except one in sporadic PD subgroup under the recessive (OR = 3.30, 95% CI: 1.23-8.84, P = 0.02) and homozygous model (OR = 3.43, 95% CI: 1.26-9.33, P = 0.02) for rs35479735.the study comprehensively evaluated the assocn. of NR4A2 variation with PD, and the results failed to demonstrate that the NR4A2 polymorphisms significantly assocd. with PD except for rs35479735, suggesting that more studies are needed to elucidate if NR4A2 is a risk of PD.
- 388Chu, Y.; Le, W.; Kompoliti, K.; Jankovic, J.; Mufson, E. J.; Kordower, J. H. Nurr1 in Parkinson’s Disease and Related Disorders. J. Comp. Neurol. 2006, 494 (3), 495– 514, DOI: 10.1002/cne.20828[Crossref], [PubMed], [CAS], Google Scholar392https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MnkvFCksA%253D%253D&md5=6cd609068c9d0996f1f8ee27a991ccc6Nurr1 in Parkinson's disease and related disordersChu Yaping; Le Weidong; Kompoliti Katie; Jankovic Joseph; Mufson Elliott J; Kordower Jeffrey HThe Journal of comparative neurology (2006), 494 (3), 495-514 ISSN:0021-9967.In mammals, the transcription factor Nurr1 is expressed early in development and continues to be detectable throughout the organism's lifetime. Nurr1 is involved in the establishment and maintenance of the dopaminergic phenotype within specific central nervous system neuronal subpopulations including the nigrostriatal dopamine system. This protein is reduced over the course of normal aging, which is a major risk factor for Parkinson's disease (PD). However, whether Nurr1 expression is affected by PD has not been documented. The present study examined the role of Nurr1 in the maintenance of the dopaminergic phenotype within neurons in substantia nigra in PD compared with patients with diagnoses of progressive supranuclear palsy (PSP) or Alzheimer's disease (AD) or age-matched-matched controls. In PD, the optical density (OD) of Nurr1 immunofluorescence was significantly decreased in nigral neurons containing alpha-synuclein-immunoreactive inclusions. Similarly, the OD of Nurr1 immunofluorescence intensity in the nigra of AD cases was decreased in neurons with neurofibrillary tangles (NFTs). In contrast to PD and AD, the OD of Nurr1 immunofluorescence intensity was severely decreased in the neurons with or without NFTs in PSP cases. Decline of Nurr1-ir neuronal number and OD was observed within substantia nigra (SN) neurons in PD but not within hippocampal neurons. The decline in Nurr1-ir expression was correlated with loss of tyrosine hydroxylase immunofluorescence across the four groups. These data demonstrate that Nurr1 deficiency in dopaminergic neurons is associated with the intracellular pathology in both synucleinopathies and tauopathies.
- 389Decressac, M.; Kadkhodaei, B.; Mattsson, B.; Laguna, A.; Perlmann, T.; Björklund, A. α-Synuclein-Induced down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons. Sci. Transl. Med. 2012, 4 (163), 163ra156, DOI: 10.1126/scitranslmed.3004676
- 390Liu, W.; Gao, Y.; Chang, N. Nurr1 Overexpression Exerts Neuroprotective and Anti-Inflammatory Roles via down-Regulating CCL2 Expression in Both in Vivo and in Vitro Parkinson’s Disease Models. Biochem. Biophys. Res. Commun. 2017, 482 (4), 1312– 1319, DOI: 10.1016/j.bbrc.2016.12.034[Crossref], [PubMed], [CAS], Google Scholar394https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFSnsL%252FE&md5=7cd2714b6d711f34e2e1c3a90d6b692dNurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 expression in both in vivo and in vitro Parkinson's disease modelsLiu, Wei; Gao, Yang; Chang, NaBiochemical and Biophysical Research Communications (2017), 482 (4), 1312-1319CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)The abnormality of nuclear receptor-related protein 1 (Nurr1) in expression and function can contribute to neurodegeneration of dopaminergic neurons and occurrence of Parkinson's disease (PD). However, its related mechanism in PD is still unknown. In this study, we found that Nurr1 was down-regulated and CCL2 was up-regulated in PD patients and PD mice. CCL2 promoted apoptosis and secretion of TNF-α and IL-1β in SH-SY5Y cells and inhibited cell viability while knockdown of CCL2 exerted the opposite effects. Nurr1 overexpression inhibited apoptosis, the release of TNF-α and IL-1β and promoted viability in α-Syn-treated SH-SY5Y cells, which was markedly promoted by CCL2 antibody and dramatically reversed by CCL2. Nurr1 overexpression neg. regulated CCL2 expression in vivo and in vitro. Furthermore, Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits and played neuroprotective and anti-inflammatory roles in MPTP-induced PD mice by down-regulating CCL2 in vivo. In conclusion, Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 in both in vivo and in vitro PD models, contributing to developing mechanism-based and neuroprotective strategies against PD.
- 391Volakakis, N.; Tiklova, K.; Decressac, M.; Papathanou, M.; Mattsson, B.; Gillberg, L.; Nobre, A.; Björklund, A.; Perlmann, T. Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression. J. Neurosci. 2015, 35 (42), 14370– 14385, DOI: 10.1523/JNEUROSCI.1155-15.2015[Crossref], [PubMed], [CAS], Google Scholar395https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xjt1Ggsr8%253D&md5=02952a6cfed6d9883e4b2358c72617d2Nurr1 and retinoid X receptor ligands stimulate Rt signaling in dopamine neurons and can alleviate α-synuclein disrupted gene expressionVolakakis, Nikolaos; Tiklova, Katarina; Decressac, Mickael; Papathanou, Maria; Mattsson, Bengt; Gillberg, Linda; Nobre, Andre; Bjoerklund, Anders; Perlmann, ThomasJournal of Neuroscience (2015), 35 (42), 14370-14385CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)α-Synuclein, a protein enriched in Lewy bodies and highly implicated in neurotoxicity in Parkinson's disease, is distributed both at nerve terminals and in the cell nucleus. Here we show that a nuclear deriv. of α-synuclein induces more pronounced changes at the gene expression level in mouse primary dopamine (DA) neurons compared to a deriv. that is excluded from the nucleus. Moreover, by RNA sequencing we analyzed the extent of genome-wide effects on gene expression resulting from expression of human α-synuclein in primary mouse DA neurons. The results implicated the transcription factor Nurr1 as a key dysregulated target of α-synuclein toxicity. Forced Nurr1 expression restored the expression of hundreds of dysregulated genes in primary DA neurons expressing α-synuclein, and therefore prompted us to test the possibility that Nurr1 can be pharmacol. targeted by bexarotene, a ligand for the retinoid X receptor that forms heterodimers with Nurr1. Although our data demonstrated that bexarotene was ineffective in neuroprotection in rats in vivo, the results revealed that bexarotene has the capacity to coregulate subsets of Nurr1 target genes including the receptor tyrosine kinase subunit Ret. Moreover, bexarotene was able to restore dysfunctional Ret-dependent neurotrophic signaling in α-synuclein-overexpressing mouse DA neurons. These data highlight the role of the Nurr1-Ret signaling pathway as a target of α-synuclein toxicity and suggest that retinoid X receptor ligands with appropriate pharmacol. properties could have therapeutic potential in Parkinson's disease.
- 392Volakakis, N.; Kadkhodaei, B.; Joodmardi, E.; Wallis, K.; Panman, L.; Silvaggi, J.; Spiegelman, B. M.; Perlmann, T. NR4A Orphan Nuclear Receptors as Mediators of CREB-Dependent Neuroprotection. Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (27), 12317– 12322, DOI: 10.1073/pnas.1007088107[Crossref], [PubMed], [CAS], Google Scholar396https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXovFyitb0%253D&md5=94e36bdc05c59c8212b562ec4fd265cfNR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotectionVolakakis, Nikolaos; Kadkhodaei, Banafsheh; Joodmardi, Eliza; Wallis, Karin; Panman, Lia; Silvaggi, Jessica; Spiegelman, Bruce M.; Perlmann, ThomasProceedings of the National Academy of Sciences of the United States of America (2010), 107 (27), 12317-12322, S12317/1-S12317/16CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Induced expression of neuroprotective genes is essential for maintaining neuronal integrity after stressful insults to the brain. Here we show that NR4A nuclear orphan receptors are induced after excitotoxic and oxidative stress in neurons, up-regulate neuro-protective genes, and increase neuronal survival. Moreover, we show that NR4A proteins are induced by cAMP response element binding protein (CREB) in neurons exposed to stressful insults and that they function as mediators of CREB-induced neuronal survival. Animals with null mutations in three of six NR4A alleles show increased oxidative damage, blunted induction of neuroprotective genes, and increased vulnerability in the hippocampus after treatment with kainic acid. We also demonstrate that NR4A and the transcriptional coactivator PGC-1α independently regulate distinct CREB-dependent neuroprotective gene programs. These data identify NR4A nuclear orphan receptors as essential mediators of neuroprotection after exposure to neuropathol. stress.
- 393Wang, X.; Zhuang, W.; Fu, W.; Wang, X.; Lv, E.; Li, F.; Zhou, S.; Rausch, W.-D.; Wang, X. The Lentiviral-Mediated Nurr1 Genetic Engineering Mesenchymal Stem Cells Protect Dopaminergic Neurons in a Rat Model of Parkinson’s Disease. Am. J. Transl. Res. 2018, 10 (6), 1583– 1599[PubMed], [CAS], Google Scholar397https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFGlu7jM&md5=f36d4eced350c7b5845a2ad11692d612The lentiviral-mediated Nurr1 genetic engineering mesenchymal stem cells protect dopaminergic neurons in a rat model of Parkinson's diseaseWang, Xiaoxiao; Zhuang, Wenxin; Fu, Wenyu; Wang, Xiaocui; Lv, E.; Li, Fengjie; Zhou, Shuanhu; Rausch, Wolf-Dieter; Wang, XinAmerican Journal of Translational Research (2018), 10 (6), 1583-1599CODEN: AJTRA7; ISSN:1943-8141. (e-Century Publishing Corp.)Nuclear receptor-related factor 1 (Nurr1) has a crucial role in the development and maturation of mesencephalic dopamine (DA) neurons and also plays a protective role in maintenance of DA neurons by inhibiting the activation of microglia and astrocyte. Moreover, the mutations in Nurr1 gene are assocd. with familial Parkinson's disease (PD), suggested that Nurr1 modulation is a potential therapeutic target for PD. This study examines the therapeutic effects of transplantation of Nurr1 gene-modified bone marrow mesenchymal stem cells (MSCs) on 6-hydroxydopamine (6-OHDA)-induced PD rat models. MSCs were transduced with lentivirus expressing Nurr1 gene and then intrastriatally transplanted into PD rats. Our results showed that Nurr1 gene-modified MSCs overexpress and secrete Nurr1 protein in vitro and also survive and migrate in the brain. Four weeks after transplantation Nurr1 gene-modified MSCs dramatically ameliorated the abnormal behavior of PD rats and increased the nos. of tyrosine hydroxylase (TH)-pos. cells in the substantia nigra (SN) and TH-pos. fibers in the striatum, inhibited the activation of glial cells, and reduced the expression of inflammatory factors in the SN. Taken together, these findings suggest that intrastriatal transplantation of lentiviral vector mediated Nurr1 gene-modified MSCs has notable therapeutic effect for PD rats.
- 394Saijo, K.; Winner, B.; Carson, C. T.; Collier, J. G.; Boyer, L.; Rosenfeld, M. G.; Gage, F. H.; Glass, C. K. A Nurr1/CoREST Pathway in Microglia and Astrocytes Protects Dopaminergic Neurons from Inflammation-Induced Death. Cell 2009, 137 (1), 47– 59, DOI: 10.1016/j.cell.2009.01.038[Crossref], [PubMed], [CAS], Google Scholar398https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXls1Srsro%253D&md5=7f2a912829a985550055d14cdb5fc9eeA Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced deathSaijo, Kaoru; Winner, Beate; Carson, Christian T.; Collier, Jana G.; Boyer, Leah; Rosenfeld, Michael G.; Gage, Fred H.; Glass, Christopher K.Cell (Cambridge, MA, United States) (2009), 137 (1), 47-59CODEN: CELLB5; ISSN:0092-8674. (Cell Press)Nurr1, an orphan nuclear receptor, plays an essential role in the generation and maintenance of dopaminergic neurons in the brain. Rare mutations in Nurr1 are assocd. with familial Parkinson's disease, but the underlying basis for this relationship has not been established. Here, we demonstrate that Nurr1 unexpectedly functions to inhibit expression of pro-inflammatory neurotoxic mediators in both microglia and astrocytes. Reduced Nurr1 expression results in exaggerated inflammatory responses in microglia that are further amplified by astrocytes, leading to the prodn. of factors that cause death of tyrosine hydroxylase-expressing neurons. Nurr1 exerts anti-inflammatory effects by docking to NF-κB-p65 on target inflammatory gene promoters in a signal-dependent manner. Subsequently, Nurr1 recruits the CoREST corepressor complex, resulting in clearance of NF-κB-p65 and transcriptional repression. These studies suggest that Nurr1 protects against loss of dopaminergic neurons in Parkinson's disease in part by limiting the prodn. of neurotoxic mediators by microglia and astrocytes.
- 395Yi, S.-H.; He, X.-B.; Rhee, Y.-H.; Park, C.-H.; Takizawa, T.; Nakashima, K.; Lee, S.-H. Foxa2 Acts as a Co-Activator Potentiating Expression of the Nurr1-Induced DA Phenotype via Epigenetic Regulation. Development 2014, 141 (4), 761– 772, DOI: 10.1242/dev.095802[Crossref], [PubMed], [CAS], Google Scholar399https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvV2nsbw%253D&md5=e62a83e3762aadea0924652011a0609fFoxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulationYi, Sang-Hoon; He, Xi-Biao; Rhee, Yong-Hee; Park, Chang-Hwan; Takizawa, Takumi; Nakashima, Kinichi; Lee, Sang-HunDevelopment (Cambridge, United Kingdom) (2014), 141 (4), 761-772CODEN: DEVPED; ISSN:0950-1991. (Company of Biologists Ltd.)Understanding how dopamine (DA) phenotypes are acquired in midbrain DA (mDA) neuron development is important for bioassays and cell replacement therapy for mDA neuron-assocd. disorders. Here, we demonstrate a feed-forward mechanism of mDA neuron development involving Nurr1 and Foxa2. Nurr1 acts as a transcription factor for DA phenotype gene expression. However, Nurr1-mediated DA gene expression was inactivated by forming a protein complex with CoREST, and then recruiting histone deacetylase 1 (Hdac1), an enzyme catalyzing histone deacetylation, to DA gene promoters. Co-expression of Nurr1 and Foxa2 was established in mDA neuron precursor cells by a pos. cross-regulatory loop. In the presence of Foxa2, the Nurr1-CoREST interaction was diminished (by competitive formation of the Nurr1-Foxa2 activator complex), and CoREST-Hdac1 proteins were less enriched in DA gene promoters. Consequently, histone 3 acetylation (H3Ac), which is responsible for open chromatin structures, was strikingly increased at DA phenotype gene promoters. These data establish the interplay of Nurr1 and Foxa2 as the crucial determinant for DA phenotype acquisition during mDA neuron development.
- 396Kim, C.-H.; Han, B.-S.; Moon, J.; Kim, D.-J.; Shin, J.; Rajan, S.; Nguyen, Q. T.; Sohn, M.; Kim, W.-G.; Han, M.; Jeong, I.; Kim, K.-S.; Lee, E.-H.; Tu, Y.; Naffin-Olivos, J. L.; Park, C.-H.; Ringe, D.; Yoon, H. S.; Petsko, G. A.; Kim, K.-S. Nuclear Receptor Nurr1 Agonists Enhance Its Dual Functions and Improve Behavioral Deficits in an Animal Model of Parkinson’s Disease. Proc. Natl. Acad. Sci. U. S. A. 2015, 112 (28), 8756– 8761, DOI: 10.1073/pnas.1509742112[Crossref], [PubMed], [CAS], Google Scholar400https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVOrs7%252FL&md5=715bbb21e39675989c84aa2ab51447dcNuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson's diseaseKim, Chun-Hyung; Han, Baek-Soo; Moon, Jisook; Kim, Deog-Joong; Shin, Joon; Rajan, Sreekanth; Nguyen, Quoc Toan; Sohn, Mijin; Kim, Won-Gon; Han, Minjoon; Jeong, Inhye; Kim, Kyoung-Shim; Lee, Eun-Hye; Tu, Yupeng; Naffin-Olivos, Jacqueline L.; Park, Chang-Hwan; Ringe, Dagmar; Yoon, Ho Sup; Petsko, Gregory A.; Kim, Kwang-SooProceedings of the National Academy of Sciences of the United States of America (2015), 112 (28), 8756-8761CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Parkinson's disease (PD), primarily caused by selective degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting 1-2% of the global population over the age of 65. Currently available pharmacol. treatments are largely symptomatic and lose their efficacy over time with accompanying severe side effects such as dyskinesia. Thus, there is an unmet clin. need to develop mechanism-based and/or disease-modifying treatments. Based on the unique dual role of the nuclear orphan receptor Nurr1 for development and maintenance of mDA neurons and their protection from inflammation-induced death, we hypothesize that Nurr1 can be a mol. target for neuroprotective therapeutic development for PD. Here we show successful identification of Nurr1 agonists sharing an identical chem. scaffold, 4-amino-7-chloroquinoline, suggesting a crit. structure-activity relationship. In particular, we found that two antimalarial drugs, amodiaquine and chloroquine stimulate the transcriptional function of Nurr1 through phys. interaction with its ligand binding domain (LBD). Remarkably, these compds. were able to enhance the contrasting dual functions of Nurr1 by further increasing transcriptional activation of mDA-specific genes and further enhancing transrepression of neurotoxic proinflammatory gene expression in microglia. Importantly, these compds. significantly improved behavioral deficits in 6-hydroxydopamine lesioned rat model of PD without any detectable signs of dyskinesia-like behavior. These findings offer proof of principle that small mols. targeting the Nurr1 LBD can be used as a mechanism-based and neuroprotective strategy for PD.
- 397Rajan, S.; Jang, Y.; Kim, C.-H.; Kim, W.; Toh, H. T.; Jeon, J.; Song, B.; Serra, A.; Lescar, J.; Yoo, J. Y.; Beldar, S.; Ye, H.; Kang, C.; Liu, X.-W.; Feitosa, M.; Kim, Y.; Hwang, D.; Goh, G.; Lim, K.-L.; Park, H. M.; Lee, C. H.; Oh, S. F.; Petsko, G. A.; Yoon, H. S.; Kim, K.-S. PGE1 and PGA1 Bind to Nurr1 and Activate Its Transcriptional Function. Nat. Chem. Biol. 2020, 16, 876– 886, DOI: 10.1038/s41589-020-0553-6[Crossref], [PubMed], [CAS], Google Scholar401https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVSgsLzI&md5=5e726ca7eff0e5ed8216d4d4bc99b4e9PGE1 and PGA1 bind to Nurr1 and activate its transcriptional functionRajan, Sreekanth; Jang, Yongwoo; Kim, Chun-Hyung; Kim, Woori; Toh, Hui Ting; Jeon, Jeha; Song, Bin; Serra, Aida; Lescar, Julien; Yoo, Jun Yeob; Beldar, Serap; Ye, Hong; Kang, Congbao; Liu, Xue-Wei; Feitosa, Melissa; Kim, Yeahan; Hwang, Dabin; Goh, Geraldine; Lim, Kah-Leong; Park, Hye Min; Lee, Choong Hwan; Oh, Sungwhan F.; Petsko, Gregory A.; Yoon, Ho Sup; Kim, Kwang-SooNature Chemical Biology (2020), 16 (8), 876-886CODEN: NCBABT; ISSN:1552-4450. (Nature Research)The orphan nuclear receptor Nurr1 is crit. for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallog. structure of Nurr1-LBD bound to PGA1 at 2.05 Å resoln. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson's disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1's transcriptional function.
- 398Bruning, J. M.; Wang, Y.; Oltrabella, F.; Tian, B.; Kholodar, S. A.; Liu, H.; Bhattacharya, P.; Guo, S.; Holton, J. M.; Fletterick, R. J.; Jacobson, M. P.; England, P. M. Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite. Cell Chem. Biol. 2019, 26 (5), 674– 685, DOI: 10.1016/j.chembiol.2019.02.002[Crossref], [PubMed], [CAS], Google Scholar402https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXks1SitLw%253D&md5=9d083c1ceca8cfb134b566ac191ef810Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine MetaboliteBruning, John M.; Wang, Yan; Oltrabella, Francesca; Tian, Boxue; Kholodar, Svetlana A.; Liu, Harrison; Bhattacharya, Paulomi; Guo, Su; Holton, James M.; Fletterick, Robert J.; Jacobson, Matthew P.; England, Pamela M.Cell Chemical Biology (2019), 26 (5), 674-685.e6CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)Nurr1, a nuclear receptor essential for the development, maintenance, and survival of midbrain dopaminergic neurons, is a potential therapeutic target for Parkinson's disease, a neurol. disorder characterized by the degeneration of these same neurons. Efforts to identify Nurr1 agonists have been hampered by the recognition that it lacks several classic regulatory elements of nuclear receptor function, including the canonical ligand-binding pocket. Here we report that the dopamine metabolite 5,6-dihydroxyindole (DHI) binds directly to and modulates the activity of Nurr1. Using biophys. assays and X-ray crystallog., we show that DHI binds to the ligand-binding domain within a non-canonical pocket, forming a covalent adduct with Cys566. In cultured cells and zebrafish, DHI stimulates Nurr1 activity, including the transcription of target genes underlying dopamine homeostasis. These findings suggest avenues for developing synthetic Nurr1 ligands to ameliorate the symptoms and progression of Parkinson's disease.
- 399Smith, G. A.; Rocha, E. M.; Rooney, T.; Barneoud, P.; McLean, J. R.; Beagan, J.; Osborn, T.; Coimbra, M.; Luo, Y.; Hallett, P. J.; Isacson, O. A Nurr1 Agonist Causes Neuroprotection in a Parkinson’s Disease Lesion Model Primed with the Toll-Like Receptor 3 DsRNA Inflammatory Stimulant Poly(I:C). PLoS One 2015, 10 (3), e0121072, DOI: 10.1371/journal.pone.0121072[Crossref], [PubMed], [CAS], Google Scholar403https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1SjtrzP&md5=b39dab5808bf6d7f94b4a78b9a42088aA Nurr1 agonist causes neuroprotection in a Parkinson-s disease lesion model primed with the toll-like receptor 3 dsRNA inflammatory stimulant poly(I:C)Smith, Gaynor A.; Rocha, Emily M.; Rooney, Thomas; Barneoud, Pascal; McLean, Jesse R.; Beagan, Jonathan; Osborn, Teresia; Coimbra, Madeleine; Luo, Yongyi; Hallett, Penelope J.; Isacson, OlePLoS One (2015), 10 (3), e0121072/1-e0121072/14CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Dopaminergic neurons in the substantia nigra pars compacta (SNpc) are characterized by the expression of genes required for dopamine synthesis, handling and reuptake and the expression of these genes is largely controlled by nuclear receptor related 1 (Nurr1). Nurr1 is also expressed in astrocytes and microglia where it functions to mitigate the release of proinflammatory cytokines and neurotoxic factors. Given that Parkinson-s disease (PD) pathogenesis has been linked to both loss of Nurr1 expression in the SNpc and inflammation, increasing levels of Nurr1 maybe a promising therapeutic strategy. In this study a novel Nurr1 agonist, SA00025, was tested for both its efficiency to induce the transcription of dopaminergic target genes in vivo and prevent dopaminergic neuron degeneration in an inflammation exacerbated 6-OHDA-lesion model of PD. SA00025 (30mg/kg p.o.) entered the brain and modulated the expression of the dopaminergic phenotype genes TH, VMAT, DAT, AADC and the GDNF receptor gene c-Ret in the SN of naive rats. Daily gavage treatment with SA00025 (30mg/kg) for 32 days also induced partial neuroprotection of dopaminergic neurons and fibers in rats administered a priming injection of polyinosinic-polycytidylic acid (poly (I:C)) and subsequent injection of 6-OHDA. The neuroprotective effects of SA00025 in this dopamine neuron degeneration model were assocd. with changes in microglial morphol. indicative of a resting state and a decrease in microglial specific IBA-1 staining intensity in the SNpc. Astrocyte specific GFAP staining intensity and IL-6 levels were also reduced.We conclude that Nurr1 agonist treatment causes neuroprotective and anti-inflammatory effects in an inflammation exacerbated 6-OHDA lesion model of PD.
- 400Zhang, Z.; Li, X.; Xie, W.; Tuo, H.; Hintermann, S.; Jankovic, J.; Le, W. Anti-Parkinsonian Effects of Nurr1 Activator in Ubiquitin-Proteasome System Impairment Induced Animal Model of Parkinson’s Disease. CNS Neurol. Disord.: Drug Targets 2012, 11 (6), 768– 773, DOI: 10.2174/187152712803581155[Crossref], [PubMed], [CAS], Google Scholar404https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlvFShug%253D%253D&md5=8ef8133d1de395f58ecb0ca0813b6b1dAnti-Parkinsonian effects of Nurr1 activator in ubiquitin-proteasome system impairment induced animal model of Parkinson's diseaseZhang, Zhen; Li, Xuping; Xie, Wen-jie; Tuo, Houzhen; Hintermann, Samuel; Jankovic, Joseph; Le, WeidongCNS & Neurological Disorders: Drug Targets (2012), 11 (6), 768-773CODEN: CNDDA3; ISSN:1871-5273. (Bentham Science Publishers Ltd.)Nurr1 is a member of the nuclear receptor superfamily and is a potential susceptibility gene for Parkinson's disease (PD). Several lines of studies in vitro and in vivo reported that defects in the Nurr1 gene cause nigrostriatal neuronal deficiency as seen in PD. In the present study, we used a a synthetic low mol. wt. Nurr1 activator which increases the transcription of Nurr1 to investigate whether it has anti-parkinsonian effects against nigrostriatal neuronal degeneration induced by proteasome inhibitor lactacystin. Adult C57BL/6 mice were treated orally with the Nurr1 activator and an inactive structural analog as a control at a dose of 10mg/kg per day, starting 3 days before microinjection of proteasome inhibitor lactacystin into the medial forebrain bundle and the treatment continued for a total of 4 wk. Animal behavior tests, and pathol. and biochem. examns. were performed to det. the anti-parkinsonian effects of the Nurr1 activator. We found that treatment with the Nurr1 activator significantly improved rotarod performance, attenuated dopamine neuron loss and nigrostriatal dopamine redn., increased expression of Nurr1, dopamine transporter and vesicular monoamine transporter 2, and alleviated microglial activation in the substantia nigra of lactacystin-lesioned mice. These results suggest that the Nurr1 activator may become an innovative strategy for the treatment of PD.
- 401Friling, S.; Bergsland, M.; Kjellander, S. Activation of Retinoid X Receptor Increases Dopamine Cell Survival in Models for Parkinson’s Disease. BMC Neurosci. 2009, 10, 146, DOI: 10.1186/1471-2202-10-146[Crossref], [PubMed], [CAS], Google Scholar405https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c%252FgtVequg%253D%253D&md5=cff519f05c894958d1c4db4996c835fdActivation of Retinoid X Receptor increases dopamine cell survival in models for Parkinson's diseaseFriling Stina; Bergsland Maria; Kjellander SusannaBMC neuroscience (2009), 10 (), 146 ISSN:.BACKGROUND: Parkinson's disease (PD) is caused by degeneration of dopamine (DA) neurons in the ventral midbrain (vMB) and results in severely disturbed regulation of movement. The disease inflicts considerable suffering for the affected and their families. Today, the opportunities for pharmacological treatment are meager and new technologies are needed. Previous studies have indicated that activation of the nuclear receptor Retinoid X Receptor (RXR) provides trophic support for DA neurons. Detailed investigations of these neurotrophic effects have been hampered by the lack of readily available DA neurons in vitro. The aim of this study was to further describe the potential neurotrophic actions of RXR ligands and, for this and future purposes, develop a suitable in vitro-platform using mouse embryonic stem cells (mESCs). RESULTS: We studied the potential neurotrophic effects of the RXR ligand LG100268 (LG268) and the RXR-Nurr1 ligand XCT0139508 (XCT) in neuronal cultures derived from rat primary vMB and mESCs. RXR ligands protect DA neurons from stress, such as that induced by the PD-modeling toxin 6-hydroxy dopamine (6-OHDA) and hypoxia, but not from stress induced by oxidative hydrogen peroxide (H2O2) or the excitotoxic agent kainic acid (KA). The neurotrophic effect is selective for DA neurons. DA neurons from rat primary vMB and mESCs behaved similarly, but the mESC-derived cultures contained a much higher fraction of DA cells and thus provided more accessible experimental conditions. CONCLUSIONS: RXR ligands rescue DA neurons from degeneration caused by the PD simulating 6-OHDA as well as hypoxia. Thus, RXR is a novel promising target for PD research. mESC-derived DA cells provide a valid and accessible in vitro-platform for studying PD inducing toxins and potential trophic agents.
- 402Spathis, A. D.; Asvos, X.; Ziavra, D.; Karampelas, T.; Topouzis, S.; Cournia, Z.; Qing, X.; Alexakos, P.; Smits, L. M.; Dalla, C.; Rideout, H. J.; Schwamborn, J. C.; Tamvakopoulos, C.; Fokas, D.; Vassilatis, D. K. Nurr1:RXRα Heterodimer Activation as Monotherapy for Parkinson’s Disease. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (15), 3999– 4004, DOI: 10.1073/pnas.1616874114[Crossref], [PubMed], [CAS], Google Scholar406https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvF2itbc%253D&md5=b1336a176bdd412897decce66f281512Nurr1:RXRα heterodimer activation as monotherapy for Parkinson's diseaseSpathis, Athanasios D.; Asvos, Xenophon; Ziavra, Despina; Karampelas, Theodoros; Topouzis, Stavros; Cournia, Zoe; Qing, Xiaobing; Alexakos, Pavlos; Smits, Lisa M.; Dalla, Christina; Rideout, Hardy J.; Schwamborn, Jens Christian; Tamvakopoulos, Constantin; Fokas, Demosthenes; Vassilatis, Demetrios K.Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (15), 3999-4004CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead mol., which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), arom. L-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.
- 403Wang, J.; Bi, W.; Zhao, W.; Varghese, M.; Koch, R. J.; Walker, R. H.; Chandraratna, R. A.; Sanders, M. E.; Janesick, A.; Blumberg, B.; Ward, L.; Ho, L.; Pasinetti, G. M. Selective Brain Penetrable Nurr1 Transactivator for Treating Parkinson’s Disease. Oncotarget 2016, 7 (7), 7469– 7479, DOI: 10.18632/oncotarget.7191[Crossref], [PubMed], [CAS], Google Scholar407https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28npt1Kltg%253D%253D&md5=43691e016c1aacf4e616678ce2fd9d84Selective brain penetrable Nurr1 transactivator for treating Parkinson's diseaseWang Jun; Bi Weina; Zhao Wei; Varghese Merina; Ward Libby; Ho Lap; Pasinetti Giulio M; Wang Jun; Pasinetti Giulio M; Koch Rick J; Walker Ruth H; Chandraratna Roshantha A; Sanders Martin E; Janesick Amanda; Blumberg BruceOncotarget (2016), 7 (7), 7469-79 ISSN:.Parkinson's disease (PD) is one of the most common movement disorders, and currently there is no effective treatment that can slow disease progression. Preserving and enhancing DA neuron survival is increasingly regarded as the most promising therapeutic strategy for treating PD. IRX4204 is a second generation retinoid X receptor (RXR) agonist that has no cross reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPARγ. We found that IRX4204 promotes the survival and maintenance of nigral dopaminergic (DA) neurons in a dose-dependent manner in primary mesencephalic cultures. Brain bioavailability studies demonstrate that IRX4204 can cross the blood brain barrier and reach the brain at nM concentration. Oral administration of IRX4204 can activate nuclear receptor Nurr1 downstream signaling in the substantia nigra (SN) andattenuate neurochemical and motor deficits in a rat model of PD. Our study suggests that IRX4204 represents a novel, potent and selective pharmacological means to activate cellular RXR-Nurr1 signaling and promote SN DA neuron survival in PD prevention and/or treatment.
- 404Loppi, S.; Kolosowska, N.; Kärkkäinen, O.; Korhonen, P.; Huuskonen, M.; Grubman, A.; Dhungana, H.; Wojciechowski, S.; Pomeshchik, Y.; Giordano, M.; Kagechika, H.; White, A.; Auriola, S.; Koistinaho, J.; Landreth, G.; Hanhineva, K.; Kanninen, K.; Malm, T. HX600, a Synthetic Agonist for RXR-Nurr1 Heterodimer Complex, Prevents Ischemia-Induced Neuronal Damage. Brain, Behav., Immun. 2018, 73, 670– 681, DOI: 10.1016/j.bbi.2018.07.021[Crossref], [PubMed], [CAS], Google Scholar408https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVersLnN&md5=9a686dd51ea3f879dd049e4db8094e70HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damageLoppi, S.; Kolosowska, N.; Karkkainen, O.; Korhonen, P.; Huuskonen, M.; Grubman, A.; Dhungana, H.; Wojciechowski, S.; Pomeshchik, Y.; Giordano, M.; Kagechika, H.; White, A.; Auriola, S.; Koistinaho, J.; Landreth, G.; Hanhineva, K.; Kanninen, K.; Malm, T.Brain, Behavior, and Immunity (2018), 73 (), 670-681CODEN: BBIMEW; ISSN:0889-1591. (Elsevier)Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were assocd. with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.
- 405Jeon, S. G.; Yoo, A.; Chun, D. W.; Hong, S. B.; Chung, H.; Kim, J.-I.; Moon, M. The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-Related Pathogenesis. Aging Dis. 2020, 11 (3), 705– 724, DOI: 10.14336/AD.2019.0718[Crossref], [PubMed], [CAS], Google Scholar409https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38rltVyrsw%253D%253D&md5=e34f6be08fe475744e1a90dd443374daThe Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer's Disease-related PathogenesisJeon Seong Gak; Yoo Anji; Chun Dong Wook; Hong Sang Bum; Moon Minho; Chung Hyunju; Kim Jin-IlAging and disease (2020), 11 (3), 705-724 ISSN:2152-5250.Several studies have revealed that the transcription factor nuclear receptor related 1 (Nurr1) plays several roles not only in the regulation of gene expression related to dopamine synthesis, but also in alternative splicing, and miRNA targeting. Moreover, it regulates cognitive functions and protects against inflammation-induced neuronal death. In particular, the role of Nurr1 in the pathogenesis of Parkinson's disease (PD) has been well investigated; for example, it has been shown that it restores behavioral and histological impairments in PD models. Although many studies have evaluated the connection between Nurr1 and PD pathogenesis, the role of Nurr1 in Alzheimer's disease (AD) remain to be studied. There have been several studies describing Nurr1 protein expression in the AD brain. However, only a few studies have examined the role of Nurr1 in the context of AD. Therefore, in this review, we highlight the overall effects of Nurr1 under the neuropathologic conditions related to AD. Furthermore, we suggest the possibility of using Nurr1 as a therapeutic target for AD or other neurodegenerative disorders.
- 406Terzioglu-Usak, S.; Negis, Y.; Karabulut, D. S.; Zaim, M.; Isik, S. Cellular Model of Alzheimer’s Disease: Aβ1–42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIβ and Nurr1 Expression. Curr. Alzheimer Res. 2017, 14 (6), 636– 644, DOI: 10.2174/1567205014666170117103217[Crossref], [PubMed], [CAS], Google Scholar410https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnsl2htrs%253D&md5=aaa13f66aa6b9e3b4918b8c2e58de6d1Cellular Model of Alzheimer';s Disease: Aβ1-42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIβ and Nurr1 ExpressionTerzioglu-Usak, Sule; Negis, Yesim; Karabulut, Derya S.; Zaim, Merve; Isik, SevimCurrent Alzheimer Research (2017), 14 (6), 636-644CODEN: CARUBY; ISSN:1567-2050. (Bentham Science Publishers Ltd.)Background: DNA topoisomerase IIβ (topo IIβ) plays a crucial role in neural differentiation and axonogenesis. Inhibition of topo IIβ activity in vitro and in vivo results in shorter axons and increased DNA damage. These mol. events also involve in Alzheimer's disease (AD); however, the role of topo IIβ in the pathogenesis of AD remains to be elucidated. Objectives: We aimed to investigate the role of topo IIβ assocn. with Nuclear receptor related 1 protein (Nurr1) in the onset of AD. Methods: In vitro AD model was established by the incubation of fibrillar amyloid-β 1-42 (Aβ1-42) for 48 h with cultured cerebellar granule neurons (CGNs) isolated from post-natal eight-day rats. The regulatory role of topo IIβ on the transcription of Nurr1 was analyzed in topo IIβ silenced CGNs, and also topo IIβ silenced and overexpressed in a neurally-differentiated human mesenchymal (hMSC) cell line. Results: Aβ1-42 fibrils led to the upregulation of Presenilin1 and Cofilin1 genes as measured at mRNA levels and hyperphosphorylation of tau protein, all are distinctive characteristics of AD pathol. A significant decrease in topo IIβ expression at mRNA and protein levels and Nurr1 at mRNA level was also obsd. In both cell types, Nurr1 expression was dramatically down-regulated due to topo IIβ deficiency, and was increased in topo IIβ overexpressing hMSCs. Conclusion: Our findings suggest that topo IIβ could be a down-stream target of signaling pathways contributing to AD-like pathol. However, further studies must be carried out in vivo to elucidate the precise assocn. topo IIβ with AD.
- 407Parra-Damas, A.; Valero, J.; Chen, M.; España, J.; Martín, E.; Ferrer, I.; Rodríguez-Alvarez, J.; Saura, C. A. Crtc1 Activates a Transcriptional Program Deregulated at Early Alzheimer’s Disease-Related Stages. J. Neurosci. 2014, 34 (17), 5776– 5787, DOI: 10.1523/JNEUROSCI.5288-13.2014[Crossref], [PubMed], [CAS], Google Scholar411https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs12iu7rN&md5=acfaea8d2b4668d95355d3935f1acaf2Crtc1 activates a transcriptional program deregulated at early Alzheimer's disease-related stagesParra-Damas, Arnaldo; Valero, Jorge; Chen, Meng; Espana, Judit; Martin, Elsa; Ferrer, Isidro; Rodriguez-Alvarez, Jose; Saura, Carlos A.Journal of Neuroscience (2014), 34 (17), 5776-5787, 12 pp.CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Cognitive decline is assocd. with gene expression changes in the brain, but the transcriptional mechanisms underlying memory impairments in cognitive disorders, such as Alzheimer's disease (AD), are largely unknown. Here, we aimed to elucidate relevant mechanisms responsible for transcriptional changes underlying early memory loss in AD by examg. pathol., behavioral, and transcriptomic changes in control and mutant β-amyloid precursor protein (APPSw,Ind) transgenic mice during aging. Genome-wide transcriptome anal. using mouse microarrays revealed deregulation of a gene network related with neurotransmission, synaptic plasticity, and learning/memory in the hippocampus of APPSw,Ind mice after spatial memory training. Specifically, APPSw,Ind mice show changes on a cAMP-responsive element binding protein (CREB)-regulated transcriptional program dependent on the CREB-regulated transcription coactivator-1 (Crtc1). Interestingly, synaptic activity and spatial memory induces Crtc1 dephosphorylation (Ser151), nuclear translocation, and Crtc1-dependent transcription in the hippocampus, and these events are impaired in APPSw,Ind mice at early pathol. and cognitive decline stages. CRTC1-dependent genes and CRTC1 levels are reduced in human hippocampus at intermediate Braak III/IV pathol. stages. Importantly, adeno-assocd. viral-mediated Crtc1 overexpression in the hippocampus efficiently reverses Aβ-induced spatial learning and memory deficits by restoring a specific subset of Crtc1 target genes. Our results reveal a crit. role of Crtc1-dependent transcription on spatial memory formation and provide the first evidence that targeting brain transcriptome reverses memory loss in AD.
- 408Moon, M.; Jeong, I.; Kim, C.-H.; Kim, J.; Lee, P. K. J.; Mook-Jung, I.; Leblanc, P.; Kim, K.-S. Correlation between Orphan Nuclear Receptor Nurr1 Expression and Amyloid Deposition in 5XFAD Mice, an Animal Model of Alzheimer’s Disease. J. Neurochem. 2015, 132 (2), 254– 262, DOI: 10.1111/jnc.12935[Crossref], [PubMed], [CAS], Google Scholar412https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFCms7o%253D&md5=59854c397dcd6079a09cef6221d60ed5Correlation between orphan nuclear receptor Nurr1 expression and amyloid deposition in 5XFAD mice, an animal model of Alzheimer's diseaseMoon, Minho; Jeong, Inhye; Kim, Chun-Hyung; Kim, Jihong; Lee, Paula K. J.; Mook-Jung, Inhee; Leblanc, Pierre; Kim, Kwang-SooJournal of Neurochemistry (2015), 132 (2), 254-262CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)The functional roles of the orphan nuclear receptor, Nurr1, have been extensively studied and well established in the development and survival of midbrain dopamine neurons. As Nurr1 and other NR4A members are widely expressed in the brain in overlapping and distinct manners, it has been an open question whether Nurr1 has important function(s) in other brain areas. Recent studies suggest that up-regulation of Nurr1 expression is crit. for cognitive functions and/or long-term memory in forebrain areas including hippocampal formation. Questions remain about the assocn. between Nurr1 expression and Alzheimer's disease (AD) brain pathol. Here, using our newly developed Nurr1-selective antibody, we report that Nurr1 protein is prominently expressed in brain areas with Aβ accumulation, i.e., the subiculum and the frontal cortex, in the 5XFAD mouse and that Nurr1 is highly co-expressed with Aβ at early stages. Furthermore, the no. of Nurr1-expressing cells significantly declines in the 5XFAD mouse in an age-dependent manner, accompanied by increased plaque deposition. Thus, our findings suggest that altered expression of Nurr1 is assocd. with AD progression. Using our newly developed Nurr1-selective antibody, we show that Nurr1 protein is prominently expressed in brain areas accumulating amyloid-beta (Aβ) in the transgenic mouse model of Alzheimer's disease (AD) and that Nurr1 is highly co-expressed with Aβ at early stages (upper panel). Furthermore, in the AD brain the no. of Nurr1-expressing cells significantly declines in an age-dependent manner concomitant with increased Aβ accumulation (lower diagram) highlighting a possible Nurr1 involvement in AD pathol.
- 409Moon, M.; Jung, E. S.; Jeon, S. G.; Cha, M.-Y.; Jang, Y.; Kim, W.; Lopes, C.; Mook-Jung, I.; Kim, K.-S. Nurr1 (NR4A2) Regulates Alzheimer’s Disease-Related Pathogenesis and Cognitive Function in the 5XFAD Mouse Model. Aging Cell 2019, 18 (1), e12866, DOI: 10.1111/acel.12866
- 410Montarolo, F.; Raffaele, C.; Perga, S.; Martire, S.; Finardi, A.; Furlan, R.; Hintermann, S.; Bertolotto, A. Effects of Isoxazolo-Pyridinone 7e, a Potent Activator of the Nurr1 Signaling Pathway, on Experimental Autoimmune Encephalomyelitis in Mice. PLoS One 2014, 9 (9), e108791, DOI: 10.1371/journal.pone.0108791[Crossref], [PubMed], [CAS], Google Scholar414https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslegtbvP&md5=bdf7ca10afd4a66a10360bb2ef394c69Effects of isoxazolo-pyridinone 7e, a potent activator of the Nurr1 signaling pathway, on experimental autoimmune encephalomyelitis in miceMontarolo, Francesca; Raffaele, Chiara; Perga, Simona; Martire, Serena; Finardi, Annamaria; Furlan, Roberto; Hintermann, Samuel; Bertolotto, AntonioPLoS One (2014), 9 (9), e108791/1-e108791/9, 9 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Multiple sclerosis (MS) is an autoimmune chronic disease of the central nervous system (CNS) characterized by immune-mediated inflammation, demyelination and subsequent axonal damage. Gene expression profiling showed that Nurr1, an orphan nuclear receptor, is down-regulated in peripheral blood mononuclear cells of MS patients. Nurr1 exerts an anti-inflammatory role repressing the activity of the pro-inflammatory transcription factor NF-kB. Here, we report that the preventive treatment with isoxazolo-pyridinone 7e, an activator of Nurr1 signaling pathway, reduces the incidence and the severity of a MS murine model, i.e. exptl. autoimmune encephalomyelitis (EAE). The compd. is able to attenuate inflammation and neurodegeneration in spinal cords of EAE mice by an NF-kB pathway-dependent process.
- 411Montarolo, F.; Perga, S.; Martire, S.; Bertolotto, A. Nurr1 Reduction Influences the Onset of Chronic EAE in Mice. Inflammation Res. 2015, 64 (11), 841– 844, DOI: 10.1007/s00011-015-0871-4[Crossref], [PubMed], [CAS], Google Scholar415https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVGnsbnP&md5=c7891a722359a2dd2a405d6cf63feafbNurr1 reduction influences the onset of chronic EAE in miceMontarolo, Francesca; Perga, Simona; Martire, Serena; Bertolotto, AntonioInflammation Research (2015), 64 (11), 841-844CODEN: INREFB; ISSN:1023-3830. (Birkhaeuser Basel)Objective: Nurr1 plays anti-inflammatory functions in astrocytes/microglia. Gene expression anal. reveals Nurr1 down-regulation in PBMCs of MS patients that neg. correlates with disease aggressiveness. This study assesses the consequences of Nurr1 redn. in a MS model represented by EAE. Methods: EAE was induced in heterozygous Nurr1 knockout mice. Clin. course was evaluated during pre-symptomatic, acute, and chronic phases. Neurohistopathol. state was analyzed in spinal cord. Results and conclusions: Nurr1 defect induces early EAE onset and increases inflammatory infiltrates in spinal cord suggesting a Nurr1 role in the early phase of EAE.
- 412Raveney, B. J. E.; Oki, S.; Yamamura, T. Nuclear Receptor NR4A2 Orchestrates Th17 Cell-Mediated Autoimmune Inflammation via IL-21 Signalling. PLoS One 2013, 8 (2), e56595, DOI: 10.1371/journal.pone.0056595[Crossref], [PubMed], [CAS], Google Scholar416https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjs12ns70%253D&md5=28d53561792eb7d317402d0177cf359bNuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signallingRaveney, Ben J. E.; Oki, Shinji; Yamamura, TakashiPLoS One (2013), 8 (2), e56595CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)IL-17-producing CD4+ T helper 17 (Th17) cells are pathogenic in a range of human autoimmune diseases and corresponding animal models. We now demonstrate that such T cells infiltrating the target organ during the induction of exptl. autoimmune encephalomyelitis (EAE) and exptl. autoimmune uveoretinitis (EAU) specifically express NR4A2. Further, we reveal a crit. involvement of NR4A2 in Th17 cell functions and Th17 cell-driven autoimmune diseases. When NR4A2 expression was blocked with siRNA, full Th17 differentiation was prevented in vitro: although cells expressed the master Th17 regulator, RORγt, they expressed reduced levels of IL-23R and were unable to produce IL-17 and IL-21. Notably, Th17 differentiation in the absence of NR4A2 was restored by exogenous IL-21, indicating that NR4A2 controls full maturation of Th17 cells via autocrine IL-21 signalling. Preventing NR4A2 expression in vivo by systemic treatment with NR4A2-specific siRNA also reduced Th17 effector responses and furthermore protected mice from EAE induction. In addn., the lack of disease was assocd. with a redn. in autocrine IL-21 prodn. and IL-23R expression. Similar modulation of NR4A2 expression was also effective as an intervention, reversing established autoimmune responses and ameliorating clin. disease symptoms. Thus, NR4A2 appears to control Th17 differentiation and so plays an essential role in the development of Th17-mediated autoimmune disease. As NR4A2 is also upregulated during human autoimmune disease, targeting NR4A2 may provide a new therapeutic approach in treating autoimmune disease.
- 413Park, T.-Y.; Jang, Y.; Kim, W.; Shin, J.; Toh, H. T.; Kim, C.-H.; Yoon, H. S.; Leblanc, P.; Kim, K.-S. Chloroquine Modulates Inflammatory Autoimmune Responses through Nurr1 in Autoimmune Diseases. Sci. Rep. 2019, 9, 15559, DOI: 10.1038/s41598-019-52085-w[Crossref], [PubMed], [CAS], Google Scholar417https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MjivFSgtQ%253D%253D&md5=35dbd549295d279d78965131b945703dChloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseasesPark Tae-Yoon; Jang Yongwoo; Kim Woori; Kim Chun-Hyung; Leblanc Pierre; Kim Kwang-Soo; Shin Joon; Toh Hui Ting; Yoon Ho Sup; Kim Kwang-SooScientific reports (2019), 9 (1), 15559 ISSN:.For over a half-century the anti-malarial drug chloroquine (CQ) has been used as a therapeutic agent, alone or in combination, to treat autoimmune diseases. However, neither the underlying mechanism(s) of action nor their molecular target(s) are well defined. The orphan nuclear receptor Nurr1 (also known as NR4A2) is an essential transcription factor affecting the development and maintenance of midbrain dopaminergic neurons. In this study, using in vitro T cell differentiation models, we demonstrate that CQ activates TREG cell differentiation and induces Foxp3 gene expression in a Nurr1-dependent manner. Remarkably, CQ appears to induce Nurr1 function by two distinct mechanisms: firstly, by direct binding to Nurr1's ligand-binding domain and promoting its transcriptional activity and secondly by upregulation of Nurr1 expression through the CREB signaling pathway. In contrast, CQ suppressed gene expression and differentiation of pathogenic TH17 cells. Importantly, using a valid animal model of inflammatory bowel disease (IBD), we demonstrated that CQ promotes Foxp3 expression and differentiation of TREG cells in a Nurr1-dependent manner, leading to significant improvement of IBD-related symptoms. Taken together, these data suggest that CQ ameliorates autoimmune diseases via regulating Nurr1 function/expression and that Nurr1 is a promising target for developing effective therapeutics of human inflammatory autoimmune diseases.
- 414Willems, S.; Ohrndorf, J.; Kilu, W.; Heering, J.; Merk, D. Fragment-like Chloroquinolineamines Activate the Orphan Nuclear Receptor Nurr1 and Elucidate Activation Mechanisms. J. Med. Chem. 2021, 64 (5), 2659– 2668, DOI: 10.1021/acs.jmedchem.0c01779[ACS Full Text], [CAS], Google Scholar418https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXkvVOlt7s%253D&md5=9cfedae7c809996347491ee53c26edd1Fragment-like Chloroquinolineamines Activate the Orphan Nuclear Receptor Nurr1 and Elucidate Activation MechanismsWillems, Sabine; Ohrndorf, Julia; Kilu, Whitney; Heering, Jan; Merk, DanielJournal of Medicinal Chemistry (2021), 64 (5), 2659-2668CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The ligand-activated transcription factor nuclear receptor related-1 (Nurr1) exhibits great potential for neurodegenerative disease treatment, but potent Nurr1 modulators to further probe and validate the nuclear receptor as a therapeutic target are lacking. We have systematically studied the structure-activity relationship of the 4-amino-7-chloroquinoline scaffold contained in Nurr1 activators amodiaquine and chloroquine and discovered fragment-like analogs that activated Nurr1 in several cellular settings. The most active descendants promoted the transcriptional activity of Nurr1 on human response elements as monomer, homodimer, and heterodimer and markedly enhanced Nurr1-dependent gene expression in human astrocytes. As a tool to elucidate mechanisms involving in Nurr1 activation, these Nurr1 agonists induced robust recruitment of NCoR1 and NCoR2 co-regulators to the Nurr1 ligand binding domain and promoted Nurr1 dimerization. These findings provide important insights in Nurr1 regulation. The fragment-sized Nurr1 agonists are appealing starting points for medicinal chem. and valuable early Nurr1 agonist tools for pharmacol. and chem. biol.
- 415de Vera, I. M. S.; Giri, P. K.; Munoz-Tello, P.; Brust, R.; Fuhrmann, J.; Matta-Camacho, E.; Shang, J.; Campbell, S.; Wilson, H. D.; Granados, J.; Gardner, W. J. J.; Creamer, T. P.; Solt, L. A.; Kojetin, D. J. Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1. ACS Chem. Biol. 2016, 11 (7), 1795– 1799, DOI: 10.1021/acschembio.6b00037[ACS Full Text], [CAS], Google Scholar419https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmvVyhsLs%253D&md5=598f95ccc2051710ed6c2662c843d8f8Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1de Vera, Ian Mitchelle S.; Giri, Pankaj K.; Munoz-Tello, Paola; Brust, Richard; Fuhrmann, Jakob; Matta-Camacho, Edna; Shang, Jinsai; Campbell, Sean; Wilson, Henry D.; Granados, Juan; Gardner, William J.; Creamer, Trevor P.; Solt, Laura. A.; Kojetin, Douglas J.ACS Chemical Biology (2016), 11 (7), 1795-1799CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Nurr1/NR4A2 is an orphan nuclear receptor, and currently there are no known natural ligands that bind Nurr1. A recent metabolomics study identified unsatd. fatty acids, including arachidonic acid and docosahexaenoic acid (DHA), that interact with the ligand-binding domain (LBD) of a related orphan receptor, Nur77/NR4A1. However, the binding location and whether these ligands bind other NR4A receptors were not defined. Here, we show that unsatd. fatty acids also interact with the Nurr1 LBD, and soln. NMR spectroscopy reveals the binding epitope of DHA at its putative ligand-binding pocket. Biochem. assays reveal that DHA-bound Nurr1 interacts with high affinity with a peptide derived from PIASγ, a protein that interacts with Nurr1 in cellular exts., and DHA also affects cellular Nurr1 transactivation. This work is the first structural report of a natural ligand binding to a canonical NR4A ligand-binding pocket and indicates a natural ligand can bind and affect Nurr1 function.
- 416de Vera, I. M. S.; Munoz-Tello, P.; Zheng, J.; Dharmarajan, V.; Marciano, D. P.; Matta-Camacho, E.; Giri, P. K.; Shang, J.; Hughes, T. S.; Rance, M.; Griffin, P. R.; Kojetin, D. J. Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1. Structure 2019, 27 (1), 66– 77, DOI: 10.1016/j.str.2018.10.002[Crossref], [PubMed], [CAS], Google Scholar420https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFCgsb3N&md5=f7b412a0b24e32cfae48ad55661f7707Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1de Vera, Ian Mitchelle S.; Munoz-Tello, Paola; Zheng, Jie; Dharmarajan, Venkatasubramanian; Marciano, David P.; Matta-Camacho, Edna; Giri, Pankaj Kumar; Shang, Jinsai; Hughes, Travis S.; Rance, Mark; Griffin, Patrick R.; Kojetin, Douglas J.Structure (Oxford, United Kingdom) (2019), 27 (1), 66-77.e5CODEN: STRUE6; ISSN:0969-2126. (Elsevier Ltd.)Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no phys. space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using soln. NMR spectroscopy, hydrogen/deuterium exchange mass spectrometry, and mol. dynamics simulations, we show that the putative canonical Nurr1 LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystd. conformation to allow binding of unsatd. fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinson's disease and schizophrenia.
- 417Windshügel, B. Structural Insights into Ligand-Binding Pocket Formation in Nurr1 by Molecular Dynamics Simulations. J. Biomol. Struct. Dyn. 2019, 37 (17), 4651– 4657, DOI: 10.1080/07391102.2018.1559099[Crossref], [PubMed], [CAS], Google Scholar421https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1Klsbo%253D&md5=ca9af61cc9aed54dead720ac8c4faf0aStructural insights into ligand-binding pocket formation in Nurr1 by molecular dynamics simulationsWindshuegel, BjoernJournal of Biomolecular Structure and Dynamics (2019), 37 (17), 4651-4657CODEN: JBSDD6; ISSN:0739-1102. (Taylor & Francis Ltd.)The nuclear receptor Nurr1 (NR4A2) has been identified as a potential target for the treatment of Parkinson's disease. In contrast to most other nuclear receptors, the X-ray crystal structure of the Nurr1 ligand-binding domain (LBD) lacks any ligand-binding pocket (LBP). However, NMR spectroscopy measurements have revealed that the known Nurr1 agonist docosahexaenoic acid (DHA) binds to a region within the LBD that corresponds to the classical NR ligand-binding pocket (LBP). In order to investigate the structural dynamics of the Nurr1 LBD and to study potential LBP formation, the conformational space of the receptor was sampled using a mol. dynamics (MD) simulation. Docking of DHA into 50,000 LBD structures extd. from the simulation revealed the existence of a transient LBP that is capable to fully harbor the compd. The location of the identified pocket overlaps with the ligand-binding site suggested by NMR expts. Structural anal. of the protein-ligand complex showed that only modest structural rearrangements within the Nurr1 LBD are required for LBP formation. These findings may support structure-based drug discovery campaigns for the development of receptor-specific agonists.
- 418Lesuisse, D.; Malanda, A.; Peyronel, J. F.; Evanno, Y.; Lardenois, P.; De-Peretti, D.; Abécassis, P.-Y.; Barnéoud, P.; Brunel, P.; Burgevin, M.-C.; Cegarra, C.; Auger, F.; Dommergue, A.; Lafon, C.; Even, L.; Tsi, J.; Luc, T. P. H.; Almario, A.; Olivier, A.; Castel, M.-N.; Taupin, V.; Rooney, T.; Vigé, X. Development of a Novel NURR1/NOT Agonist from Hit to Lead and Candidate for the Potential Treatment of Parkinson’s Disease. Bioorg. Med. Chem. Lett. 2019, 29 (7), 929– 932, DOI: 10.1016/j.bmcl.2019.01.024[Crossref], [PubMed], [CAS], Google Scholar422https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjt1Sqtbg%253D&md5=20b882a19d4c0db9abf47f45dfbc8b61Development of a novel NURR1/NOT agonist from hit to lead and candidate for the potential treatment of Parkinson's diseaseLesuisse, Dominique; Malanda, Andre; Peyronel, Jean-Francois; Evanno, Yannick; Lardenois, Patrick; De-Peretti, Danielle; Abecassis, Pierre-Yves; Barneoud, Pascal; Brunel, Pascale; Burgevin, Marie-Claude; Cegarra, Celine; Auger, Florian; Dommergue, Amelie; Lafon, Corinne; Even, Luc; Tsi, Joanna; Luc, Thy Phuong Hieu; Almario, Antonio; Olivier, Anne; Castel, Marie-Noelle; Taupin, Veronique; Rooney, Thomas; Vige, XavierBioorganic & Medicinal Chemistry Letters (2019), 29 (7), 929-932CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)In the course of a program aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson's disease, a few hits from high throughput screening were identified and characterized. A combined optimization pointed to a very narrow and stringent structure activity relationship. A comprehensive program of optimization led to a potent and safe candidate drug displaying neuroprotective and anti-inflammatory activity in several in vitro and in vivo models.
- 419Almario Garcia, A.; Lardenois, P.; Olivier, A. Derivatives of 2-Aryl-6-Phenyl-Imid Azo [1, 2-α]Pyridines, Their Preparation and Their Therapeutic Use. WO2008/034974A1. Sanofi-Aventis, 2008.
- 420Malanda, A.; Abécassis, P.-Y.; Barnéoud, P.; Brunel, P.; Taupin, V.; Vigé, X.; Lesuisse, D. Data on Synthesis, ADME and Pharmacological Properties and Early Safety Pharmacology Evaluation of a Series of Novel NURR1/NOT Agonist Potentially Useful for the Treatment of Parkinson’s Disease. Data Br. 2019, 27, 104057, DOI: 10.1016/j.dib.2019.104057
- 421Dubois, C.; Hengerer, B.; Mattes, H. Identification of a Potent Agonist of the Orphan Nuclear Receptor Nurr1. ChemMedChem 2006, 1 (9), 955– 958, DOI: 10.1002/cmdc.200600078[Crossref], [PubMed], [CAS], Google Scholar425https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVCmu7o%253D&md5=cf81e4fdb1410b826f77479f61f0c30cIdentification of a potent agonist of the orphan nuclear receptor Nurr1Dubois, Celine; Hengerer, Bastian; Mattes, HenriChemMedChem (2006), 1 (9), 955-958CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Mimotope's SynPhase double lanterns were used for the development of a six-step synthesis of benzimidazoles. A library of 3840 benzimidazoles was prepd. on Mimotope's double lanterns using the sort-and-combine strategy. A no. of micromolar agonists of Nurr1, which increased the luciferase reporter-gene activity by a factor of 2, could be identified by screening the first generation library of 3256 compds. To improve the potency of the first-generation hits, we designed and synthesized a second-generation library biased toward Nurr1. Very potent Nurrl agonists (e.g. I ) were thus rapidly identified by designing, synthesizing, and screening a first-generation library oriented toward nuclear receptors, followed by a small, biased second-generation library.
- 422Hintermann, S.; Chiesi, M.; von Krosigk, U.; Mathé, D.; Felber, R.; Hengerer, B. Identification of a Series of Highly Potent Activators of the Nurr1 Signaling Pathway. Bioorg. Med. Chem. Lett. 2007, 17 (1), 193– 196, DOI: 10.1016/j.bmcl.2006.09.062[Crossref], [PubMed], [CAS], Google Scholar426https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXislSg&md5=8cb547a0ff17183aaef9a87dd1db29efIdentification of a series of highly potent activators of the Nurr1 signaling pathwayHintermann, Samuel; Chiesi, Michele; von Krosigk, Ulrike; Mathe, Daniele; Felber, Richard; Hengerer, BastianBioorganic & Medicinal Chemistry Letters (2007), 17 (1), 193-196CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The nuclear receptor Nurr1 (NR4A2) is critically involved in the development and maintenance of midbrain dopaminergic neurons and is believed to function independently of endogenous activation. The hit identification and SAR studies leading to isoxazolo-pyridinone 7e (I), a highly potent, brain penetrable activator of the Nurr1 signaling pathway, are described.
- 423Li, X.; Lee, S.-O.; Safe, S. Structure-Dependent Activation of NR4A2 (Nurr1) by 1,1-Bis(3′- Indolyl)-1-(Aromatic)Methane Analogs in Pancreatic Cancer Cells. Biochem. Pharmacol. 2012, 83 (10), 1445– 1455, DOI: 10.1016/j.bcp.2012.02.021[Crossref], [PubMed], [CAS], Google Scholar427https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktFGitbY%253D&md5=c2a6e2dfb65f41fe9aa193af7335d25eStructure-dependent activation of NR4A2 (Nurr1) by 1,1-bis(3'-indolyl)-1-(aromatic)methane analogs in pancreatic cancer cellsLi, Xi; Lee, Syng-Ook; Safe, StephenBiochemical Pharmacology (2012), 83 (10), 1445-1455CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)NR4A2 (Nurr1) is an orphan nuclear receptor with no known endogenous ligands and is highly expressed in many cancer cell lines including Panc1 and Panc28 pancreatic cancer cells. Structure-dependent activation of NR4A2 by a series of 1,1-bis(3'-indolyl)-1-(arom.)methane (C-DIM) analogs was detd. in pancreatic cancer cells transfected with yeast GAL4-Nurr1 chimeras and a UASx5-luc reporter gene or constructs contg. response elements that bind NR4A2. Among 23 different structural analogs, Ph groups contg. p-substituted trifluoromethyl, t-Bu, cyano, bromo, iodo and trifluoromethoxy groups were the most active compds. in transactivation assay. The p-bromophenyl analog (DIM-C-pPhBr) was used as a model for structure-activity studies among a series of ortho-, meta- and para-bromophenyl isomers and the corresponding indole 2- and N-Me analogs. Results show that NR4A2 activation was maximal with the p-bromophenyl analog and methylation of the indole NH group abrogated activity. Moreover, using GAL4-Nurr1 (full length) or GAL-Nurr1-A/B and GAL4-Nurr1-(C-F) chimeras expressing N- and C-terminal domains of Nurr1, resp., DIM-C-pPhBr activated all three constructs and these responses were differentially affected by kinase inhibitors. DIM-C-pPhBr also modulated expression of several Nurr1-regulated genes in pancreatic cancer cells including vasoactive intestinal peptide (VIP), and the immunohistochem. and western blot analyses indicated that DIM-C-pPhBr activates nuclear NR4A2.
- 424Inamoto, T.; Papineni, S.; Chintharlapalli, S.; Cho, S. D.; Safe, S.; Kamat, A. M. 1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane Activates the Orphan Nuclear Receptor Nurr1 and Inhibits Bladder Cancer Growth. Mol. Cancer Ther. 2008, 7 (12), 3825– 3833, DOI: 10.1158/1535-7163.MCT-08-0730[Crossref], [PubMed], [CAS], Google Scholar428https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsV2iurbK&md5=1cfbb9b8327fcd644d5eb996b79e2e691,1-Bis(3'-indolyl)-1-(p-chlorophenyl)methane activates the orphan nuclear receptor Nurr1 and inhibits bladder cancer growthInamoto, Teruo; Papineni, Sabitha; Chintharlapalli, Sudhakar; Cho, Sung-Dae; Safe, Stephen; Kamat, Ashish M.Molecular Cancer Therapeutics (2008), 7 (12), 3825-3833CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Nurr1 is an orphan nuclear receptor and a member of the nerve growth factor I-B subfamily of transcription factors with no known endogenous ligand or stimulator. We show, for the first time, evidence that Nurr1 is expressed in a panel of 11 human bladder cancer cell lines. A new class of methylene-substituted diindolylmethanes (C-DIM) were screened and 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (DIM-C-pPhCl) activated the ligand-binding domain of Nurr1. Treatment of bladder cancer cells with Nurr1-active C-DIM resulted in decreased cell survival (MTT assay) and induction of cell death pathways, resulting in poly(ADP-ribose) polymerase cleavage and DNA fragmentation. The specificity of the Nurr1-active compd. was shown using RNA interference in 253J B-V cells, whereby small interfering RNA against Nurr1 attenuated ligand-dependent activation of Nurr1 and poly(ADP-ribose) polymerase cleavage. Furthermore, activation of Nurr1 resulted in stimulation of tumor necrosis factor-related apoptosis-inducing ligand and small interfering RNA expts. attenuated tumor necrosis factor-related apoptosis-inducing ligand prodn. In an orthotopic model of human bladder tumors established in nude mice, administration of a Nurr1-active C-DIM suppressed bladder cancer growth. These results identify Nurr1 as a potential target for bladder cancer therapy and also identify a novel agent for activating Nurr1.
- 425De Miranda, B. R.; Popichak, K. A.; Hammond, S. L.; Miller, J. A.; Safe, S.; Tjalkens, R. B. Novel Para-Phenyl Substituted Diindolylmethanes Protect against MPTP Neurotoxicity and Suppress Glial Activation in a Mouse Model of Parkinson’s Disease. Toxicol. Sci. 2015, 143 (2), 360– 373, DOI: 10.1093/toxsci/kfu236[Crossref], [PubMed], [CAS], Google Scholar429https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFGlt7c%253D&md5=338bb8a7a471bc88999ac934ee168fa0Novel para-phenyl substituted diindolylmethanes protect against MPTP neurotoxicity and suppress glial activation in a mouse model of Parkinson's diseaseDe Miranda, Briana R.; Popichak, Katriana A.; Hammond, Sean L.; Miller, James A.; Safe, Stephen; Tjalkens, Ronald B.Toxicological Sciences (2015), 143 (2), 360-373CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)The orphan nuclear receptor NR4A2 (Nurr1) constitutively regulates inflammatory gene expression in glial cells by suppressing DNA binding activity of NF-κB. We recently reported that novel 1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methane (C-DIM) compds. that activate NR4A family nuclear receptors in cancer lines also suppress inflammatory gene expression in primary astrocytes and prevent loss of dopaminergic neurons in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp). In this study, we postulated that the basis for this neuroprotection involves blockade of glial activation and subsequent expression of NF-κB-regulated inflammatory genes. To examine this mechanism, we treated transgenic NF-κB/EGFP reporter mice with MPTPp for 7 days (MPTPp7d) followed by daily oral gavage with either vehicle (corn oil; MPTPp14d) or C-DIMs contg. p-methoxyphenyl (C-DIM5), p-hydroxyphenyl (C-DIM8), or p-chlorophenyl (C-DIM12) groups. Each compd. conferred significant protection against progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), even when given after 7 days of dosing with MPTPp. C-DIM12 had the greatest neuroprotective activity in MPTPp-treated mice, and was also the most potent compd. in suppressing activation of microglia and astrocytes, expression of cytokines and chemokines in quant. polymerase chain reaction (qPCR) array studies, and in reducing expression of NF-κB/EGFP in the SN. C-DIM12 prevented nuclear export of Nurr1 in dopaminergic neurons and enhanced expression of the Nurr1-regulated proteins tyrosine hydroxylase and the dopamine transporter. These data indicate that NR4A-active C-DIM compds. protect against loss of dopamine neurons in the MPTPp model of PD by preventing glial-mediated neuronal injury and by supporting a dopaminergic phenotype in TH-pos. neurons in the SNpc.
- 426Hammond, S. L.; Safe, S.; Tjalkens, R. B. A Novel Synthetic Activator of Nurr1 Induces Dopaminergic Gene Expression and Protects against 6-Hydroxydopamine Neurotoxicity in Vitro. Neurosci. Lett. 2015, 607, 83– 89, DOI: 10.1016/j.neulet.2015.09.015[Crossref], [PubMed], [CAS], Google Scholar430https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1SlurnJ&md5=0d9a83edeeec515918023b330ab72f50A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitroHammond, Sean L.; Safe, Stephen; Tjalkens, Ronald B.Neuroscience Letters (2015), 607 (), 83-89CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Degeneration of dopaminergic neurons in Parkinson's disease (PD) is assocd. with decreased expression of the orphan nuclear receptor Nurr1 (NR4A2), which is crit. for both homeostasis and development of dopamine (DA) neurons. The synthetic, phytochem.-based compd., 1,1-bis (3'-indolyl)-1-(p-chlorophenyl) methane (C-DIM12) activates Nurr1 in cancer cells and prevents loss of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice. In the present study, we examd. the capacity of C-DIM12 to induce expression of Nurr1-regulated genes in two dopaminergic neuronal cell lines (N2A, N27) and to protect against 6-hydroxydopamine (6-OHDA) neurotoxicity. C-DIM12 induced expression of Nurr1-regulated genes that was abolished by Nurr1 knockdown. C-DIM12 increased expression of transfected human Nurr1, induced Nurr1 protein expression in primary dopaminergic neurons and enhanced neuronal survival from exposure to 6-OHDA. These data indicate that C-DIM12 stimulates neuroprotective expression Nurr1-regulated genes in DA neurons.
- 427Hammond, S. L.; Tjalkens, R. B.; Safe, S.; Richman, E. H.; Backos, D. S.; Li, X.; Hunt, L. G.; Chong, E.; Popichak, K. A.; Damale, P. The Nurr1 Ligand,1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism. J. Pharmacol. Exp. Ther. 2018, 365 (3), 636– 651, DOI: 10.1124/jpet.117.246389[Crossref], [PubMed], [CAS], Google Scholar431https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVCntb3O&md5=77dd95db62e674cd310b56a041be2b89The Nurr1 ligand,1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane, modulates glial reactivity and is neuroprotective in MPTP-induced parkinsonismsHammond, Sean L.; Popichak, Katriana A.; Li, Xi; Hunt, Lindsay G.; Richman, Evan H.; Damale, Pranav U.; Chong, Edwin K. P.; Backos, Donald S.; Safe, Stephen; Tjalkens, Ronald B.Journal of Pharmacology and Experimental Therapeutics (2018), 365 (3), 636-651CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)We postulated that the activation of Nurr1 would suppress the activation of glia and thereby protect against loss of DA neurons after subacute lesioning with MPTP. Our previous studies have shown that a synthetic Nurr1 ligand, C-DIM12, suppresses inflammatory gene expression in primary astrocytes and induces a dopaminergic phenotype in neurons. Pharmacokinetic anal. of C-DIM12 in mice by liq. chromatog.-mass spectrometry demonstrated that approx. three times more compd. concd. in the brain than in plasma. Mice treated with four doses of MPTP + probenecid over 14 days were monitored for neurobehavioral function, loss of dopaminergic neurons, and glial activation. C-DIM12 protected against the loss of DA neurons in the substantia nigra pars compacta and DA terminals in the striatum, maintained a ramified phenotype in microglia, and suppressed activation of astrocytes. In vitro reporter assays demonstrated that C-DIM12 was an effective activator of Nurr1 transcription in neuronal cell lines. Computational modeling of C-DIM12 binding to the three-dimensional structure of human Nurr1 identified a high-affinity binding interaction with Nurr1 at the coactivator domain. Taken together, these data suggest that C-DIM12 is an activator of Nurr1 that suppresses glial activation and neuronal loss in vivo after treatment with MPTP, and that this receptor could be an efficacious target for disease modification in individuals with Parkinson's disease and related disorders.
- 428Karki, K.; Li, X.; Jin, U.-H.; Mohankumar, K.; Zarei, M.; Michelhaugh, S. K.; Mittal, S.; Tjalkens, R.; Safe, S. Nuclear Receptor 4A2 (NR4A2) Is a Druggable Target for Glioblastomas. J. Neuro-Oncol. 2020, 146 (1), 25– 39, DOI: 10.1007/s11060-019-03349-y[Crossref], [PubMed], [CAS], Google Scholar432https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlCitb7P&md5=c59faaf59f390c4f657c058a44ff8791Nuclear receptor 4A2 (NR4A2) is a druggable target for glioblastomasKarki, Keshav; Li, Xi; Jin, Un-Ho; Mohankumar, Kumaravel; Zarei, Mahsa; Michelhaugh, Sharon K.; Mittal, Sandeep; Tjalkens, Ronald; Safe, StephenJournal of Neuro-Oncology (2020), 146 (1), 25-39CODEN: JNODD2; ISSN:0167-594X. (Springer)Introduction: The orphan nuclear receptor 4A2 (NR4A2) has been extensively characterized in subcellular regions of the brain and is necessary for the function of dopaminergic neurons. The NR4A2 ligand, 1,1-bis (31-indoly1)-1-(p-chlorophenyl)methane (DIM-C-pPhCl) inhibits markers of neuroinflammation and degeneration in mouse models and in this study we investigated expression and function of NR4A2 in glioblastoma (GBM). Established and patient-derived cell lines were used as models and the expression and functions of NR4A2 were detd. by western blots and NR4A2 gene silencing by antisense oligonucleotides resp. Effects of NR4A2 knockdown and DIM-C-pPhCl on cell growth, induction of apoptosis (Annexin V Staining) and migration/invasion (Boyden chamber and spheroid invasion assay) and transactivation of NR4A2-regulated reporter genes were detd. Tumor growth was investigated in athymic nude mice bearing U87-MG cells as xenografts. NR4A2 knockdown and DIM-C-pPhCl inhibited GBM cell and tumor growth, induced apoptosis and inhibited migration and invasion of GBM cells. DIM-C-pPhCl and related analogs also inhibited NR4A2-regulated transactivation (luciferase activity) confirming that DIM-C-pPhCl acts as an NR4A2 antagonist and blocks NR4A2-dependent pro-oncogenic responses in GBM. Conclusion: We demonstrate for the first time that NR4A2 is pro-oncogenic in GBM and thus a potential druggable target for patients with tumors expressing this receptor. Moreover, our bis-indole-derived NR4A2 antagonists represent a novel class of anti-cancer agents with potential future clin. applications for treating GBM.
- 429De Miranda, B. R.; Miller, J. A.; Hansen, R. J.; Lunghofer, P. J.; Safe, S.; Gustafson, D. L.; Colagiovanni, D.; Tjalkens, R. B. Neuroprotective Efficacy and Pharmacokinetic Behavior of Novel Anti-Inflammatory Para-Phenyl Substituted Diindolylmethanes in a Mouse Mdel of Parkinson’s Disease. J. Pharmacol. Exp. Ther. 2013, 345 (1), 125– 138, DOI: 10.1124/jpet.112.201558[Crossref], [PubMed], [CAS], Google Scholar433https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlsVyrs7c%253D&md5=35f561028811c12226919fd1bc44adafNeuroprotective efficacy and pharmacokinetic behavior of novel anti-inflammatory para-phenyl substituted diindolylmethanes in a mouse model of Parkinson's diseaseDe Miranda, Briana R.; Miller, James A.; Hansen, Ryan J.; Lunghofer, Paul J.; Safe, Stephen; Gustafson, Daniel L.; Colagiovanni, Dorothy; Tjalkens, Ronald B.Journal of Pharmacology and Experimental Therapeutics (2013), 345 (1), 125-138CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)There are currently no registered drugs that slow the progression of neurodegenerative diseases, in part because translation from animal models to the clinic has been hampered by poor distribution to the brain. The present studies examd. a selected series of para-phenyl-substituted diindolylmethane (C-DIM) compds. that display anti-inflammatory and neuroprotective efficacy in vitro. We postulated that the pharmacokinetic behavior of C-DIM compds. after oral administration would correlate with neuroprotective efficacy in vivo in a mouse model of Parkinson's disease. Pharmacokinetics and metab. of 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (C-DIM5), 1,1-bis(3'-indolyl)-1-(phenyl)methane, 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (C-DIM8), and 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) were detd. in plasma and brain of C57Bl/6 mice after oral and i.v. administration at 10 and 1 mg/Kg, resp. Putative metabolites were measured in plasma, liver, and urine. C-DIM compds. given orally displayed the highest area under the curve, Cmax, and Tmax levels, and C-DIM12 exhibited the most favorable pharmacokinetics of the compds. tested. Oral bioavailability of each compd. ranged from 6% (C-DIM8) to 42% (C-DIM12). After pharmacokinetic studies, the neuroprotective efficacy of C-DIM5, C-DIM8, and C-DIM12 (50 mg/Kg per oral) was examd. in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid for 14 days, a model of progressive neurodegeneration with a strong neuroinflammatory component. C-DIM5 and C-DIM12 given orally once daily after one week of exposure to MPTP and probenecid prevented further loss of dopaminergic neurons in the substantia nigra pars compacta and striatal dopamine terminals, indicating that these compds. could be effective therapeutic agents to prevent neurodegeneration.
- 430Hibino, S.; Chikuma, S.; Kondo, T.; Ito, M.; Nakatsukasa, H.; Omata-Mise, S.; Yoshimura, A. Inhibition of Nr4a Receptors Enhances Antitumor Immunity by Breaking Treg-Mediated Immune Tolerance. Cancer Res. 2018, 78 (11), 3027– 3040, DOI: 10.1158/0008-5472.CAN-17-3102[Crossref], [PubMed], [CAS], Google Scholar434https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVKjsb%252FK&md5=8121148b58f88e18a3eead1fe7c50522Inhibition of Nr4a receptors enhances antitumor immunity by breaking Treg-mediated immune toleranceHibino, Sana; Chikuma, Shunsuke; Kondo, Taisuke; Ito, Minako; Nakatsukasa, Hiroko; Omata-Mise, Setsuko; Yoshimura, AkihikoCancer Research (2018), 78 (11), 3027-3040CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Enhanced infiltration of regulatory T cells (Treg) into tumor tissue is detrimental to patients with cancer and is closely assocd. with poor prognosis as they create an immunosuppressive state that suppresses antitumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here, we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg genetic programs, contribute to Treg-mediated suppression of antitumor immunity in the tumor microenvironment. Mice lacking Nr4a1 and Nr4a2 genes specifically in Tregs showed resistance to tumor growth in transplantation models without exhibiting any severe systemic autoimmunity. The chemotherapeutic agent camptothecin and a common cyclooxygenase-2 inhibitor were found to inhibit transcriptional activity and induction of Nr4a factors, and they synergistically exerted antitumor effects. Genetic inactivation or pharmacol. inhibition of Nr4a factors unleashed effector activities of CD8+ cytotoxic T cells and evoked potent antitumor immune responses. These findings demonstrate that inactivation of Nr4a in Tregs breaks immune tolerance toward cancer, and pharmacol. modulation of Nr4a activity may be a novel cancer treatment strategy targeting the immunosuppressive tumor microenvironment.
- 431Komiya, T.; Yamamoto, S.; Roy, A.; McDonald, P.; Perez, R. P. Drug Screening to Target Nuclear Orphan Receptor NR4A2 for Cancer Therapeutics. Transl. Lung Cancer Res. 2017, 6 (5), 600– 610, DOI: 10.21037/tlcr.2017.07.02[Crossref], [PubMed], [CAS], Google Scholar435https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2htrvJ&md5=b00932577e658f7561d7ee820fc02eeeDrug screening to target nuclear orphan receptor NR4A2 for cancer therapeuticsKomiya, Takefumi; Yamamoto, Satomi; Roy, Anuradha; McDonald, Peter; Perez, Raymond P.Translational Lung Cancer Research (2017), 6 (5), 600-610CODEN: TLCRA9; ISSN:2226-4477. (Pioneer Bioscience Publishing Co.)Our previous study suggested NR4A2, a subfamily member of orphan nuclear receptors, is essential for survival of human cancer cells such as mucoepidermoid carcinoma (MEC). We conducted high throughput drug screening for NR4A2 inhibitors as a novel therapeutic modality. Pos. screening was performed using a luciferase reporter vector contg. NR4A2 binding sequence, and a CRE-reporter control vector was used to eliminate false positives. In vitro assays for pos. hits were conducted. A total of 23 Food and Drug Administration (FDA) and 43 Life Science Library compds. were identified, including several epidermal growth factor inhibitors and Src inhibitors. Subsequent in vitro assays confirmed that identified compds. were preferentially active in NR4A2+ cancer cells. Several candidate compds. appeared to suppress NR4A2 via inhibition of p-ERK, whereas a novel compd. KU0171309 may act as a more direct inhibitor. Further research should focus on homolog selectivity, in vivo activity, and definitively deciphering the mechanism of action of KU0171309.
- 432Pan, T.; Xie, W.; Jankovic, J.; Le, W. Biological Effects of Pramipexole on Dopaminergic Neuron-Associated Genes: Relevance to Neuroprotection. Neurosci. Lett. 2005, 377 (2), 106– 109, DOI: 10.1016/j.neulet.2004.11.080[Crossref], [PubMed], [CAS], Google Scholar436https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhvVCrs74%253D&md5=02be75fd630d4d3269573743eb7f0780Biological effects of pramipexole on dopaminergic neuron-associated genes: relevance to neuroprotectionPan, Tianhong; Xie, Wenjie; Jankovic, Joseph; Le, WeidongNeuroscience Letters (2005), 377 (2), 106-109CODEN: NELED5; ISSN:0304-3940. (Elsevier Ltd.)Pramipexole (PRX) is a nonergot dopamine (DA) D2/D3 receptor agonist. Exptl. studies have provided evidence that PRX may exert neuroprotective effects on the nigro-striatal system. Recent studies have demonstrated a slower decline of DAT d. in Parkinson's disease patients treated with PRX as measured by SPECT. The aim of this study is to det. whether PRX has direct biol. effects on DAergic neuron-assocd. genes expression, including DAT, VMAT2, and Nurr1. The human neuroblastoma SH-SY5Y cells were treated with PRX for various time periods and harvested to measure the mRNA and protein products of these genes. Treatment with PRX at 10 μM significantly increased DAT mRNA levels by 54-130% in 4-8 h, VMAT2 mRNA levels by 34% in 4 h, and Nurr1 mRNA levels by 31-39% in 2-4 h, which was the earliest induction among these three genes. The protein levels of DAT, VMAT2, and Nurr1 were markedly increased after PRX treatment, among which the increase of Nurr1 protein level was the highest at first 2 h treatment of PRX. Nafadotride, a D3 DA receptor antagonist, blocked the increase of Nurr1 gene expression induced by PRX, while eticlopride, a D2 DA receptor antagonist, did not show this effect. The findings that PRX has biol. regulatory effects on DAergic neuron-assocd. genes may explain both the slower decline of imaged DAT and the neuroprotective effect of PRX. Furthermore, our results suggest that the induction of Nurr1 gene expression by PRX may be mediated by D3 DA receptor.
- 433Hedya, S. A.; Safar, M. M.; Bahgat, A. K. Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD Model. Mol. Neurobiol. 2018, 55 (9), 7579– 7587, DOI: 10.1007/s12035-018-0923-1[Crossref], [PubMed], [CAS], Google Scholar437https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXis1aktrc%253D&md5=0819fa052b325f29fbbecf5237007c78Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD ModelHedya, Shireen A.; Safar, Marwa M.; Bahgat, Ashraf K.Molecular Neurobiology (2018), 55 (9), 7579-7587CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Nuclear receptor related 1 (Nurr1) orphan receptor has emerged as a promising contender in ameliorating Parkinson's disease; thus, finding a suitable activator of Nurr1 receptor is an attracting target for treating PD. Cilostazol, a phosphodiesterase-3 inhibitor, recently showed a favorable neuroprotective activity in multiple devastating central disorders, yet the possible antiparkinsonian activity of the drug has not been fully elucidated. Thus, the aim of this study is to explore the neuroprotective effect of cilostazol in rotenone-induced PD model in rats. Cilostazol successfully upregulated Nurr1 expression in PD rats, which resulted in successful preservation of the dopaminergic neuron functionality and integrity as verified by the marked improvement of motor performance in rotarod and open field tests, as well as the increased striatal tyrosine hydroxylase content. Moreover, cilostazol revealed an anti-inflammatory activity as manifested by hampering the global controller of inflammatory signaling pathway, nuclear factor-kappa B, together with its downstream pro-inflammatory cytokines, namely tumor necrosis factor-alpha and interleukin-1 beta, via Nurr-1 upregulation and glycogen synthase kinase 3 beta GSK-3β inhibition. In turn, the increase in GSK-3β inhibited form suppressed the measured downstream apoptotic biomarkers, viz. cytochrome C and caspase-3. Remarkably, cilostazol enhanced autophagy as depicted by hampering both LC3-II and P62 levels possibly through the prominent rise in sirtuin 1 level. In conclusion, cilostazol could be a promising candidate for PD treatment through modulating Nurr1 expression, as well as SIRT-1/autophagy, and GSK-3β/apoptosis cross-regulation. [Figure not available: see fulltext.].
- 434Ham, A.; Lee, H. J.; Hong, S. S.; Lee, D.; Mar, W. Moracenin D from Mori Cortex Radicis Protects SH-SY5Y Cells against Dopamine-Induced Cell Death by Regulating Nurr1 and α-Synuclein Expression. Phytother. Res. 2012, 26 (4), 620– 624, DOI: 10.1002/ptr.3592[Crossref], [PubMed], [CAS], Google Scholar438https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xlt1artrw%253D&md5=8960a11e5614b814b3c8f0ed02011863Moracenin D from Mori Cortex Radicis Protects SH-SY5Y Cells against Dopamine-induced Cell Death by Regulating Nurr1 and α-Synuclein ExpressionHam, Ahrom; Lee, Hak Ju; Hong, Seong Su; Lee, Dongho; Mar, WoongchonPhytotherapy Research (2012), 26 (4), 620-624CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)In our efforts to find neuroprotective materials of plant origin, several compds. were isolated from Mori Cortex Radicis. The protective effect against dopamine-induced cell death was examd., and the subsequent effects on the levels of expression of Parkinson's disease-assocd. nurr1 and α-synuclein were evaluated in a dopamine-induced system. Five compds. were isolated and moracenin D protected cell death against dopamine-induction in human neuroblastoma SH-SY5Y cells. The effects of moracenin D on the levels of mRNA and protein expression of nurr1 and α-synuclein were subsequently examd. using reverse transcription-polymerase chain reaction (RT-PCR) and western blot anal. Treatment with moracenin D resulted in an up-regulation of nurr1 mRNA levels and a down-regulation of α-synuclein mRNA levels. Addnl., the α-synuclein protein expression was decreased in accordance with an increase in nurr1 protein expression. These results demonstrate that the protective effects of moracenin D were presumably due to the correlative effects on the up-regulation of nurr1 and down-regulation of α-synuclein expressions against dopamine induction. Therefore, moracenin D can be considered as a candidate for therapy for Parkinson's disease. Copyright © 2011 John Wiley & Sons, Ltd.
- 435Wallén-Mackenzie, Å.; De Urquiza, A. M.; Petersson, S.; Rodriguez, F. J.; Friling, S.; Wagner, J.; Ordentlich, P.; Lengqvist, J.; Heyman, R. A.; Arenas, E.; Perlmann, T. Nurr1-RXR Heterodimers Mediate RXR Ligand-Induced Signaling in Neuronal Cells. Genes Dev. 2003, 17 (24), 3036– 3047, DOI: 10.1101/gad.276003[Crossref], [PubMed], [CAS], Google Scholar439https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhs1Shtg%253D%253D&md5=775b3bea209013c2a9c5f616a26ecd9dNurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cellsWallen-Mackenzie, Asa; Mata de Urquiza, Alexander; Petersson, Susanna; Rodriguez, Francisco J.; Friling, Stina; Wagner, Joseph; Ordentlich, Peter; Lengqvist, Johan; Heyman, Richard A.; Arenas, Ernest; Perlmann, ThomasGenes & Development (2003), 17 (24), 3036-3047CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)The retinoid X receptor (RXR) is essential as a common heterodimerization partner of several nuclear receptors (NRs). However, its function as a bona fide receptor for endogenous ligands has remained poorly understood. Such a role would depend on the existence of RXR activating ligands in vivo and on the ability of such ligands to influence relevant biol. functions. Here we demonstrate the presence of endogenous RXR ligands in the embryonic central nervous system (CNS) and show that they can activate heterodimers formed between RXR and the orphan NR Nurr1 in vivo. Moreover, RXR ligands increase the no. of surviving dopaminergic cells and other neurons in a process mediated by Nurr1-RXR heterodimers. These results provide evidence for a role of Nurr1 as a ligand-independent partner of RXR in its function as a bona fide ligand-activated NR. Finally, our findings identify RXR-Nurr1 heterodimers as a potential target in the treatment of neurodegenerative disease.
- 436Morita, K.; Kawana, K.; Sodeyama, M.; Shimomura, I.; Kagechika, H.; Makishima, M. Selective Allosteric Ligand Activation of the Retinoid X Receptor Heterodimers of NGFI-B and Nurr1. Biochem. Pharmacol. 2005, 71 (1–2), 98– 107, DOI: 10.1016/j.bcp.2005.10.017[Crossref], [PubMed], [CAS], Google Scholar440https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1OlsLrM&md5=8364846e8af567e47a35eacaa8c1dbd2Selective allosteric ligand activation of the retinoid X receptor heterodimers of NGFI-B and Nurr1Morita, Kentaro; Kawana, Katsuyoshi; Sodeyama, Mariko; Shimomura, Iichiro; Kagechika, Hiroyuki; Makishima, MakotoBiochemical Pharmacology (2005), 71 (1-2), 98-107CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)NGFI-B, an orphan member of the NR4A subfamily of the nuclear receptors, recognizes specific sequences in the promoters of neuronal target genes as a monomer. Although NGFI-B also forms a heterodimer with the retinoid X receptor (RXR), a receptor for 9-cis retinoic acid (9CRA), endogenous targets of the heterodimer have not been identified. We investigated the role of RXR ligand binding in NGFI-B/RXR activation and found that dibenzodiazepine-derived ligands, such as the weak RXR agonist HX600, selectively activate NGFI-B/RXR heterodimers. HX600 also activated the heterodimer formed by RXR and Nurr1, another NR4A subfamily receptor. In an assembly assay that detects ligand-dependent reconstruction of the ligand-binding domain, HX600 and not 9CRA induced an allosteric ligand effect on NGFI-B through RXRα binding. The data indicate that the RXR heterodimers of NGFI-B and Nurr1 are selectively activated by the RXR ligand HX600, and that compds. such as HX600 will be valuable tools in investigating NGFI-B and Nurr1 function.
- 437Ishizawa, M.; Kagechika, H.; Makishima, M. NR4A Nuclear Receptors Mediate Carnitine Palmitoyltransferase 1A Gene Expression by the Rexinoid HX600. Biochem. Biophys. Res. Commun. 2012, 418 (4), 780– 785, DOI: 10.1016/j.bbrc.2012.01.102[Crossref], [PubMed], [CAS], Google Scholar441https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitFyjtb8%253D&md5=630f2c03f912772d376790865252f01aNR4A nuclear receptors mediate carnitine palmitoyltransferase 1A gene expression by the rexinoid HX600Ishizawa, Michiyasu; Kagechika, Hiroyuki; Makishima, MakotoBiochemical and Biophysical Research Communications (2012), 418 (4), 780-785CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and can be activated by 9-cis retinoic acid (9CRA). RXRs form homodimers and heterodimers with other nuclear receptors such as the retinoic acid receptor and NR4 subfamily nuclear receptors, Nur77 and NURR1. Potential physiol. roles of the Nur77-RXR and NURR1-RXR heterodimers have not been elucidated. In this study, the authors identified a gene regulated by these heterodimers utilizing HX600, a selective RXR agonist for Nur77-RXR and NURR1-RXR. While 9CRA induced many genes, including RAR-target genes, HX600 effectively induced only carnitine palmitoyltransferase 1A (CPT1A) in human teratocarcinoma NT2/D1 cells, which express RXRα, Nur77 and NURR1. HX600 also increased CPT1A expression in human embryonic kidney (HEK) 293 cells and hepatocyte-derived HepG2 cells. Although HX600 induced CPT1A less effectively than 9CRA, overexpression of Nur77 or NURR1 increased the HX600 response to levels similar to 9CRA in NT2/D1 and HEK293 cells. A dominant-neg. form of Nur77 or NURR1 repressed the induction of CPT1A by HX600. A protein synthesis inhibitor did not alter HX600-dependent CPT1A induction. Thus, the rexinoid HX600 directly induces expression of CPT1A through a Nur77 or NURR1-mediated mechanism. CPT1A, a gene involved in fatty acid β-oxidn., could be a target of RXR-NR4 receptor heterodimers.
- 438Sundén, H.; Schäfer, A.; Scheepstra, M.; Leysen, S.; Malo, M.; Ma, J.-N.; Burstein, E. S.; Ottmann, C.; Brunsveld, L.; Olsson, R. Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation. J. Med. Chem. 2016, 59 (3), 1232– 1238, DOI: 10.1021/acs.jmedchem.5b01702[ACS Full Text], [CAS], Google Scholar442https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVWlsro%253D&md5=64a2afc980aa80962992640a486a5710Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer ActivationSunden, Henrik; Schaefer, Anja; Scheepstra, Marcel; Leysen, Seppe; Malo, Marcus; Ma, Jian-Nong; Burstein, Ethan S.; Ottmann, Christian; Brunsveld, Luc; Olsson, RogerJournal of Medicinal Chemistry (2016), 59 (3), 1232-1238CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist I at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where I optimally addresses the ligand binding pocket of RXR.
- 439Scheepstra, M.; Andrei, S. A.; de Vries, R. M. J. M.; Meijer, F. A.; Ma, J.-N.; Burstein, E. S.; Olsson, R.; Ottmann, C.; Milroy, L.-G.; Brunsveld, L. Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization. ACS Chem. Neurosci. 2017, 8 (9), 2065– 2077, DOI: 10.1021/acschemneuro.7b00216[ACS Full Text], [CAS], Google Scholar443https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCju7nP&md5=665fbd39142e946b3fdf097a345675f2Ligand Dependent Switch from RXR Homo- to RXR-NURR1 HeterodimerizationScheepstra, Marcel; Andrei, Sebastian A.; de Vries, Rens M. J. M.; Meijer, Femke A.; Ma, Jian-Nong; Burstein, Ethan S.; Olsson, Roger; Ottmann, Christian; Milroy, Lech-Gustav; Brunsveld, LucACS Chemical Neuroscience (2017), 8 (9), 2065-2077CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Retinoid X Receptors (RXRs) play key roles in many physiol. processes in both the periphery and central nervous system. In addn., RXRs form heterodimers with other nuclear receptors to exert their physiol. effects. The Nuclear Receptor Related 1 protein (NURR1) is particularly interesting because of its role in promoting differentiation and survival of dopamine neurons. However only a small no. of RXR-heterodimer selective modulators are available, with limited chem. diversity. This work describes the synthesis, biochem. evaluation and structural elucidation of a novel series of RXR ligands with strongly biased interactions with RXRα-NURR1 heterodimers. Targeted modifications to the small mol. biaryl scaffold caused local RXRα side-chain disturbances and displacement of secondary structural elements upon ligand binding. This resulted in the repositioning of protein helixes in the heterodimer interface of RXRα, alterations in homo- vs. heterodimer formation, and modulation of activation function 2 (AF2). The data provide a rationale for the design of RXR ligands consisting of a highly conserved hydrophilic region, strongly contributing to the ligand affinity, and a variable hydrophobic region, which efficiently probes the effects of structural changes at the level of the ligand on co-regulator recruitment or the RXRα-NURR1 dimerization interface.
- 440McFarland, K.; Spalding, T. A.; Hubbard, D.; Ma, J.-N.; Olsson, R.; Burstein, E. S. Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson’s Disease. ACS Chem. Neurosci. 2013, 4 (11), 1430– 1438, DOI: 10.1021/cn400100f[ACS Full Text], [CAS], Google Scholar444https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1SgsLrN&md5=54d129a78f986304f82ea3f723202129Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson's DiseaseMcFarland, Krista; Spalding, Tracy A.; Hubbard, David; Ma, Jian-Nong; Olsson, Roger; Burstein, Ethan S.ACS Chemical Neuroscience (2013), 4 (11), 1430-1438CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Nurr1 is a nuclear hormone receptor (NucHR) strongly implicated in the growth, maintenance, and survival of dopaminergic neurons. Nurr1 may be unable to bind ligands directly, but it forms heterodimers with other NucHRs that do. Using bioluminescence resonance energy transfer (BRET) assays to directly monitor interactions of Nurr1 with other NucHRs, we found the cancer drug bexarotene (Targretin, also LGD1069) displayed biased interactions with Nurr1-RXR heterodimers compared with RXR-RXR homodimers. Remarkably, at doses up to 100-fold lower than those effective in rodent cancer models, bexarotene rescued dopamine neurons and reversed behavioral deficits in 6-hydroxydopamine (6-OHDA) lesioned rats. Compared to the high doses used in cancer therapy, low doses of bexarotene have significantly milder side effects including a reduced increase in plasma triglycerides and less suppression of thyroid function. On the basis of extrapolations from rat to human doses, we hypothesize that low oral doses of bexarotene may provide an effective and tolerated therapy for Parkinson's disease (PD).
- 441Pönniö, T.; Conneely, O. M. Nor-1 Regulates Hippocampal Axon Guidance, Pyramidal Cell Survival, and Seizure Susceptibility. Mol. Cell. Biol. 2004, 24 (20), 9070– 9078, DOI: 10.1128/MCB.24.20.9070-9078.2004[Crossref], [PubMed], [CAS], Google Scholar445https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cvovVKqsg%253D%253D&md5=101cd310a3e866ffcc7acf8f7597f495nor-1 regulates hippocampal axon guidance, pyramidal cell survival, and seizure susceptibilityPonnio Tiia; Conneely Orla MMolecular and cellular biology (2004), 24 (20), 9070-8 ISSN:0270-7306.The nuclear receptor transcription factor, nor-1, is expressed during mammalian development predominantly in the nervous system and is induced in a cell-specific manner in nonneuronal cells in response to a variety of extracellular stimuli. To elucidate the essential developmental functions of this transcription factor, we have analyzed the consequences of its elimination on central nervous system development in mice. Here we show that null mutant mice lacking nor-1 respond with increased limbic seizure activity to the excitotoxic glutamate receptor agonist kainic acid. We demonstrate that these abnormalities are associated with defective postnatal hippocampal development exemplified by abnormal axonal guidance of dentate gyrus granule and mossy cells, disorganization of the pyramidal cell layer, and early postnatal death of pyramidal neurons in the CA1 field of the hippocampus. Our data indicate that nor-1 plays a critical role in neuronal survival and axonal guidance in the developing murine hippocampus and that hippocampal dysgenesis in nor-1-/- mice may be an underlying cause of seizure susceptibility.
- 442Ferrán, B.; Martí-Pàmies, I.; Alonso, J.; Rodríguez-calvo, R.; Aguiló, S.; Vidal, F.; Rodríguez, C.; Martínez-gonzález, J. The Nuclear Receptor NOR-1 Regulates the Small Muscle Protein, X-Linked (SMPX) and Myotube Differentiation. Sci. Rep. 2016, 6, 25944, DOI: 10.1038/srep25944[Crossref], [PubMed], [CAS], Google Scholar446https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XotFOjsr8%253D&md5=eeb6a3bd40da22f70e570f575593ee07The nuclear receptor NOR-1 regulates the small muscle protein, X-linked (SMPX) and myotube differentiationFerran, Beatriz; Marti-Pamies, Ingrid; Alonso, Judith; Rodriguez-Calvo, Ricardo; Aguilo, Silvia; Vidal, Francisco; Rodriguez, Cristina; Martinez-Gonzalez, JoseScientific Reports (2016), 6 (), 25944CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Recent works have highlighted the role of NOR-1 in both smooth and skeletal muscle, and have proposed this nuclear receptor as a nexus that coordinates muscle performance and metabolic capacity. However, no muscle specific genes regulated by NOR-1 have been identified so far. To identify NOR-1 target genes, we over-expressed NOR-1 in human vascular smooth muscle cells (VSMC). These cells subjected to sustained over-expression of supraphysiol. levels of NOR-1 experienced marked phenotypic changes and up-regulated the skeletal muscle protein X-linked (SMPX), a protein typically expressed in striated muscle and assocd. to cell shape. By transcriptional studies and DNA-protein binding assays, we identified a non-consensus NBRE site in human SMPX promoter, crit. for NOR-1 responsiveness. The expression of SMPX was higher in human skeletal muscle myoblasts (HSMM) than in human VSMC, and further increased in HSMM differentiated to myotubes. NOR-1 silencing prevented SMPX expression in HSMM, as well as their differentiation to myotubes, but the up-regulation of SMPX was dispensable for HSMM differentiation. Our results indicate that NOR-1 regulate SMPX in human muscle cells and acts as a muscle regulatory factor, but further studies are required to unravel its role in muscle differentiation and hypertrophy.
- 443Kon, T.; Miki, Y.; Tanji, K.; Mori, F.; Tomiyama, M.; Toyoshima, Y.; Kakita, A.; Takahashi, H.; Utsumi, J.; Sasaki, H.; Wakabayashi, K. Localization of Nuclear Receptor Subfamily 4, Group A, Member 3 (NR4A3) in Lewy Body Disease and Multiple System Atrophy. Neuropathology 2015, 35 (6), 503– 509, DOI: 10.1111/neup.12210[Crossref], [PubMed], [CAS], Google Scholar447https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFKrurnO&md5=e3185f1e84fdfefb9c5e610839545e21Localization of nuclear receptor subfamily 4, group A, member 3 (NR4A3) in Lewy body disease and multiple system atrophyKon, Tomoya; Miki, Yasuo; Tanji, Kunikazu; Mori, Fumiaki; Tomiyama, Masahiko; Toyoshima, Yasuko; Kakita, Akiyoshi; Takahashi, Hitoshi; Utsumi, Jun; Sasaki, Hidenao; Wakabayashi, KoichiNeuropathology (2015), 35 (6), 503-509CODEN: NOPAFH; ISSN:1440-1789. (John Wiley & Sons, Inc.)Nuclear receptor subfamily 4, group A, member 3 (NR4A3), also known as neuron-derived orphan receptor-1, is a nuclear receptor which plays key roles in cell cycle, neuronal differentiation, apoptosis and metab. These processes may be involved in the pathogenesis of certain neurodegenerative diseases. Previous studies have shown that there are high levels of NR4A3 mRNA in the CNS. Moreover, NR4A2, a transcription factor with homol. to NR4A3, has been reported to contribute to the pathogenesis of Parkinson's disease. However, it is uncertain whether NR4A3 is also involved in diseases such as dementia with Lewy bodies, multiple system atrophy, and other neurodegenerative disorders such as tauopathies, TDP-43 proteinopathies and polyglutamine diseases. In the present study we used immunohistochem. to examine the brain and spinal cord from patients with various neurodegenerative diseases and normal control subjects using two polyclonal anti-NR4A3 antibodies. In controls, the cytoplasm of neurons and glial cells was faintly immunostained with anti-NR4A3 antibodies. In tissues from patients with neurodegenerative diseases, immunoreactivity for NR4A3 was obsd. in cortical and brainstem-type Lewy bodies in Parkinson's disease and in dementia with Lewy bodies, as well as in neuronal and glial cytoplasmic inclusions in multiple system atrophy. A double-labeled immunofluorescence study showed co-localization of NR4A3 and phosphorylated α-synuclein in these inclusions. Neuronal and glial inclusions in other neurodegenerative disorders were NR4A3 neg. These findings suggest that accumulation of NR4A3 is specific to α-synucleinopathy.
- 444Maheux, J.; Ethier, I.; Rouillard, C.; Levesque, D. Induction Patterns of Transcription Factors of the Nur Family (Nurr1, Nur77, and Nor −1) by Typical and Atypical Antipsychotics in the Mouse Brain : Implication for Their Mechanism of Action. J. Pharmacol. Exp. Ther. 2005, 313 (1), 460– 473, DOI: 10.1124/jpet.104.080184[Crossref], [PubMed], [CAS], Google Scholar448https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjtlSnt7g%253D&md5=8442134083ae68da2a546c90c9fc70ecInduction patterns of transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) by typical and atypical antipsychotics in the mouse brain: Implication for their mechanism of actionMaheux, Jerome; Ethier, Isabelle; Rouillard, Claude; Levesque, DanielJournal of Pharmacology and Experimental Therapeutics (2005), 313 (1), 460-473CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Monitoring gene expression has been intensively used to identify neurobiol. and neuroanatomical substrates assocd. with administration of antipsychotic drugs. Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors that have been recently assocd. with dopamine neurotransmission. Nurr1 is involved in midbrain dopamine neuron development. Nur77 and Nor-1 are expressed in dopaminoceptive areas such as the striatum, nucleus accumbens, and prefrontal cortex. To better understand the relationship between Nur and antipsychotic drug effects, we conducted a comprehensive evaluation of the effect of various typical and atypical antipsychotic drugs on the modulation of Nur mRNA levels. We show that differential patterns of Nur expression can be obtained with typical and atypical antipsychotic drugs. Modulation of Nur77 and Nor-1 mRNA expression by antipsychotics can be used to calc. an index that is predictive of the typical or atypical profile of antipsychotic drugs. Inductions of Nur by antipsychotic drugs are correlated with dopamine D2 receptor in the striatum and D2 and D3 receptor subtypes in the nucleus accumbens. The 5-hydroxytryptamine2A/D2 affinity ratio of antipsychotics can also predict these patterns of inductions. In addn. to classical gene patterns induced in the striatal complex (striatum, accumbens) and cortex, most antipsychotic drugs tested strongly induced Nur77, Nor-1, and increased Nurr1 mRNA levels in the substantia nigra and ventral tegmental area. These data suggest that typical and atypical antipsychotic drugs might induce in multiple brain regions distinct Nur-dependent transcriptional activities, which may contribute to their pharmacol. effects.
- 445DeYoung, R. A.; Baker, J. C.; Cado, D.; Winoto, A. The Orphan Steroid Receptor Nur77 Family Member Nor-1 Is Essential for Early Mouse Embryogenesis. J. Biol. Chem. 2003, 278 (47), 47104– 47109, DOI: 10.1074/jbc.M307496200[Crossref], [PubMed], [CAS], Google Scholar449https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXovFKktL4%253D&md5=a379cbc1e20a0637a782e7bb55107c42The orphan steroid receptor Nur77 family member Nor-1 is essential for early mouse embryogenesisDeYoung, R. Andrea; Baker, Julie C.; Cado, Dragana; Winoto, AstarJournal of Biological Chemistry (2003), 278 (47), 47104-47109CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Nur77 and its family members, Nor-1 and Nurr1, are orphan steroid receptors implicated in a wide variety of biol. processes, including apoptosis and dopamine neuron agenesis. Expression of these family members can be detected at low levels in many tissues but they are expressed at very high levels when cells are stimulated by outside signals, including serum, nerve growth factor, and receptor engagement. Introduction of a dominant neg. Nur77 protein that blocks the activities of all family members led to inhibition of apoptosis in T cells. Nur77-deficient mice, however, exhibit no phenotype, and a line of Nor-1 mutant mice was reported to exhibit a mild ear development phenotype but no other gross abnormalities. Here, we report the generation of Nor-1-deficient mice with a block in early embryonic development. Nor-1 is expressed early during embryogenesis, and its loss leads to embryonic lethality around embryonic day 8.5 of gestation. The mutant embryos fail to complete gastrulation and display distinct morphol. abnormalities, including a decrease in overall size, developmental delay and an accumulation of mesoderm in the primitive streak during gastrulation. Abnormal expression of a no. of early developmental markers and defects in growth or distribution of emerging mesoderm cells were also detected. These data suggest that Nor-1 plays a crucial role in gastrulation.
- 446Chio, C.-C.; Wei, L.; Chen, T. G.; Lin, C.-M.; Shieh, J.-P.; Yeh, P.-S.; Chen, R.-M. Neuron-Derived Orphan Receptor 1 Transduces Survival Signals in Neuronal Cells in Response to Hypoxia-Induced Apoptotic Insults. J. Neurosurg. 2016, 124 (6), 1654– 1664, DOI: 10.3171/2015.6.JNS1535[Crossref], [PubMed], [CAS], Google Scholar451https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1Chsb3L&md5=333f467992ebd27714f3595884ea122fNeuron-derived orphan receptor 1 transduces survival signals in neuronal cells in response to hypoxia-induced apoptotic insultsChio, Chung-Ching; Wei, Li; Chen, Tyng Guey; Lin, Chien-Min; Shieh, Ja-Ping; Yeh, Poh-Shiow; Chen, Ruei-MingJournal of Neurosurgery (2016), 124 (6), 1654-1664CODEN: JONSAC; ISSN:0022-3085. (American Association of Neurosurgeons)Objective Hypoxia can induce cell death or trigger adaptive mechanisms to guarantee cell survival. Neuron-derived orphan receptor 1 (NOR-1) works as an early-response protein in response to a variety of environmental stresses. In this study, the authors evaluated the roles of NOR-1 in hypoxia-induced neuronal insults. Methods Neuro-2a cells were exposed to oxygen/glucose deprivation (OGD). Cell viability, cell morphol., cas-pase-3 activity, DNA fragmentation, and cell apoptosis were assayed to det. the mechanisms of OGD-induced neuronal insults. RNA and protein analyses were carried out to evaluate the effects of OGD on expressions of NOR-1, cAMP response element-binding (CREB), and cellular inhibitor of apoptosis protein 2 (cIAP2) genes. Translations of these gene expressions were knocked down using RNA interference. Mice subjected to traumatic brain injury (TBI) and NOR-1 was immunodetected. Results Exposure of neuro-2a cells to OGD decreased cell viability in a time-dependent manner. Addnl., OGD led to cell shrinkage, DNA fragmentation, and cell apoptosis. In parallel, treatment of neuro-2a cells with OGD time dependently increased cellular NOR-1 mRNA and protein expressions. Interestingly, administration of TBI also augmented NOR-1 levels in the impacted regions of mice. As to the mechanism, exposure to OGD increased nuclear levels of the transcription factor CREB protein. Downregulating CREB expression using RNA interference simultaneously inhibited OGD-induced NOR-1 mRNA expression. Also, levels of cIAP2 mRNA and protein in neuro-2a cells were augmented by OGD. After reducing cIAP2 translation, OGD-induced cell death was reduced. Sequentially, application of NOR-1 small interfering RNA to neuro-2a cells significantly inhibited OGD-induced cIAP2 mRNA expression and concurrently alleviated hypoxia-induced alterations in cell viability, caspase-3 activation, DNA damage, and cell apoptosis. Conclusions This study shows that NOR-1 can transduce survival signals in neuronal cells responsible for hypoxia-induced apoptotic insults through activation of a CREB/cIAP2-dependent mechanism.
- 447Kagaya, S.; Ohkura, N.; Tsukada, T.; Miyagawa, M.; Sugita, Y.; Tsujimoto, G.; Matsumoto, K.; Saito, H.; Hashida, R. Prostaglandin A 2 Acts as a Transactivator for NOR1 (NR4A3) within the Nuclear Receptor Superfamily. Biol. Pharm. Bull. 2005, 28 (9), 1603– 1607, DOI: 10.1248/bpb.28.1603[Crossref], [PubMed], [CAS], Google Scholar452https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFWjur3N&md5=ce8958564731cc5897bf6bb265f3d664Prostaglandin A2 acts as a transactivator for NOR1 (NR4A3) within the nuclear receptor superfamilyKagaya, Shinji; Ohkura, Naganari; Tsukada, Toshihiko; Miyagawa, Masami; Sugita, Yuji; Tsujimoto, Gozoh; Matsumoto, Kenji; Saito, Hirohisa; Hashida, RyoichiBiological & Pharmaceutical Bulletin (2005), 28 (9), 1603-1607CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)Within the nuclear receptor superfamily, Nur77, Nurr1, and NOR1 constitute the nuclear receptor subfamily 4 group A. Modulation of NOR1 function would be therapeutic potential for diseases related to dysfunction of NOR1, including extraskeletal myxoid chondrosarcoma and autoimmune diseases. By screening arachidonate metabolites for their capacity of transcriptional activation, we have identified prostaglandin (PG) A2 as a transactivator for NOR1. PGA2 acted as a potent activator of NOR1-dependent transcription through the GAL4-based reporter system. The putative ligand-binding domain (LBD) of the receptor directly bound PGA2, and LBD-deleted receptor showed little transcriptional activation by PGA2. Primary cultured spleen cells derived from transgenic mice overexpressing NOR1, showed higher sensitivity to PGA2 compared to those from wild-type mice. These observations suggest that PGA2 can serve as a transactivator of NOR1, and thus suggest a possibility of pharmacol. modulation of the NOR1 pathways by PGA2-related compds.
- 448Eyster, K. M. The Estrogen Receptors: An Overview from Different Perspectives. In Methods in Molecular Biology; Humana Press Inc., 2016; Vol. 1366, pp 1– 10.
- 449Dahlman-Wright, K.; Cavailles, V.; Fuqua, S. A.; Jordan, V. C.; Katzenellenbogen, J. A.; Korach, K. S.; Maggi, A.; Muramatsu, M.; Parker, M. G.; Gustafsson, J.-Å. International Union of Pharmacology. LXIV. Estrogen Receptors. Pharmacol. Rev. 2006, 58 (4), 773– 781, DOI: 10.1124/pr.58.4.8[Crossref], [PubMed], [CAS], Google Scholar456https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkt1aisA%253D%253D&md5=bf6fbc877371c6611a2ba612f11d05f0International union of pharmacology. LXIV. Estrogen receptorsDahlman-Wright, Karin; Cavailles, Vincent; Fuqua, Suzanne A.; Jordan, V. Craig; Katzenellenbogen, John A.; Korach, Kenneth S.; Maggi, Adriana; Muramatsu, Masami; Parker, Malcolm G.; Gustafsson, Jan-AakePharmacological Reviews (2006), 58 (4), 773-781CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. A review discusses the mechanism of transcriptional activation and functional roles of estrogen receptors in physiol. and disease. It also tackles structural features of the ligand-binding domain and current evaluation of SERMs as medicines.
- 450Hewitt, S. C.; Korach, K. S. Estrogen Receptors: New Directions in the New Millennium. Endocr. Rev. 2018, 39 (5), 664– 675, DOI: 10.1210/er.2018-00087[Crossref], [PubMed], [CAS], Google Scholar457https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mbnt1CmsQ%253D%253D&md5=f3e205139f5c634223569c1006c060acEstrogen Receptors: New Directions in the New MillenniumHewitt Sylvia C; Korach Kenneth SEndocrine reviews (2018), 39 (5), 664-675 ISSN:.Nineteen years have passed since our previous review in this journal in 1999 regarding estrogen receptors. At that time, we described the current assessments of the physiological activities of estrogen and estrogen receptors. Since that time there has been an explosion of progress in our understanding of details of estrogen receptor-mediated processes from the molecular and cellular level to the whole organism. In this review we discuss the basic understanding of estrogen signaling and then elaborate on the progress and current understanding of estrogen receptor actions that have developed using new models and continuing clinical studies.
- 451Dupont, S.; Krust, A.; Gansmuller, A.; Dierich, A.; Chambon, P.; Mark, M. Effect of Single and Compound Knockouts of Estrogen Receptors Alpha (ERalpha) and Beta (ERbeta) on Mouse Reproductive Phenotypes. Development 2000, 127 (19), 4277– 4291, DOI: 10.1242/dev.127.19.4277[Crossref], [PubMed], [CAS], Google Scholar458https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXotVWisbY%253D&md5=b19ca01d70bf99b001292b3bb7161169Effect of single and compound knockouts of estrogen receptors α (ERα) and β (ERβ) on mouse reproductive phenotypesDupont, Sonia; Krust, Andree; Gansmuller, Anne; Dierich, Andree; Chambon, Pierre; Mark, ManuelDevelopment (Cambridge, United Kingdom) (2000), 127 (19), 4277-4291CODEN: DEVPED; ISSN:0950-1991. (Company of Biologists Ltd.)The functions of estrogen receptors (ERs) in mouse ovary and genital tracts were investigated by generating null mutants for ERα (ERαKO), ERβ (ERβKO) and both ERs (ERαβKO). All ERαKO females are sterile, whereas ERβKO females are either infertile or exhibit variable degrees of subfertility. Mast cells present in adult ERαKO and ERαβKO ovaries could participate in the generation of hemorrhagic cysts. Folliculogenesis proceeds normally up to the large antral stage in both ERαKO and ERβKO adults, whereas large antral follicles of ERα+/-/ERβKO and ERαβKO adults are markedly deficient in granulosa cells. Similarly, prematurely developed follicles found in prepubertal ERαKO ovaries appear normal, but their ERαβKO counterparts display only few granulosa cell layers. Upon superovulation treatment, all prepubertal ERαKO females form numerous preovulatory follicles of which the vast majority do not ovulate. The same treatment fails to elicit the formation of preovulatory follicles in half of the ERβKO mice and in all ERα+/-/ERβKO mice. These and other results reveal a functional redundancy between ERα and ERβ for ovarian folliculogenesis, and strongly suggest that ERβ plays an important role in mediating the stimulatory effects of estrogens on granulosa cell proliferation, ERα is not required for follicle growth under wild type conditions, while it is indispensable for ovulation, and ERα is also necessary for interstitial glandular cell development. The authors' data also indicate that ERβ exerts some function in ERαKO uterus and vagina. ERαβKO granulosa cells localized within degenerating follicles transform into cells displaying junctions that are unique to testicular Sertoli cells. From the distribution pattern of anti-Mullerian hormone (AMH) in ERαβKO ovaries, it is unlikely that an elevated AMH level is the cause of Sertoli cell differentiation. The authors' results also show that cell proliferation in the prostate and urinary bladder of old ERβKO and ERαβKO males is apparently normal.
- 452Lan, Y.-L.; Zhao, J.; Li, S. Update on the Neuroprotective Effect of Estrogen Receptor Alpha Against Alzheimer’s Disease. J. Alzheimer's Dis. 2015, 43 (4), 1137– 1148, DOI: 10.3233/JAD-141875[Crossref], [PubMed], [CAS], Google Scholar459https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFalt7zE&md5=491a95dc15d88d857a5219463bce4778Update on the Neuroprotective Effect of Estrogen Receptor Alpha Against Alzheimer's DiseaseLan, Yu-Long; Zhao, Jie; Li, ShaoJournal of Alzheimer's Disease (2015), 43 (4), 1137-1148CODEN: JADIF9; ISSN:1387-2877. (IOS Press)A review. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and disordered cognition. Women have a higher AD incidence than men, indicating that the declining estrogen levels during menopause may influence AD pathogenesis. However, the mechanism underlying estrogen's neuroprotective effect is not fully clarified and is complicated by the presence of several distinct estrogen receptor (ER) types and the identification of a growing no. of ER splice variants. Thus, a deeper anal. of ERs could elucidate the role of estrogen in age-related cognitive changes. Intracellular calcium signaling cascades play a pivotal role in ERα neuroprotection against AD. The ERα-mediated inhibition of Death domain-assocd. protein (Daxx) translocation and the combination of membrane ERα and caveolin in caveolae may protect against AD. Moreover, the voltage-dependent anion channel (VDAC)/ERα assocn. may be important for maintaining channel inactivation and may be relevant in neuronal preservation against Aβ injury. Addnl., ERα may prevent glutamate excitotoxic injury by Aβ through estrogen signaling mechanisms. ERα and IGF-IR co-activation may mediate neuroprotection, and many other growth factors and intracellular signaling responses triggered by ERα may also play important roles in this process. Furthermore, details regarding the genes and mRNA variants of ERα that are expressed in different parts of the human organs have been clarified recently. Therefore, here we review the literature to clarify the neuroprotective role of ERα. This review focuses on the potential mechanisms mediated by ERα in the intracellular signaling events in nervous system cells, thereby clarifying ERα-mediated protection against AD.
- 453Chakrabarti, M.; Haque, A.; Banik, N. L.; Nagarkatti, P.; Nagarkatti, M.; Ray, S. K. Estrogen Receptor Agonists for Attenuation of Neuroinflammation and Neurodegeneration. Brain Res. Bull. 2014, 109, 22– 31, DOI: 10.1016/j.brainresbull.2014.09.004[Crossref], [PubMed], [CAS], Google Scholar460https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Wjsr%252FK&md5=a9f6710232c3b28dcb6316bd863bba6cEstrogen receptor agonists for attenuation of neuroinflammation and neurodegenerationChakrabarti, Mrinmay; Haque, Azizul; Banik, Naren L.; Nagarkatti, Prakash; Nagarkatti, Mitzi; Ray, Swapan K.Brain Research Bulletin (2014), 109 (), 22-31CODEN: BRBUDU; ISSN:0361-9230. (Elsevier)Recent results from lab. investigations and clin. trials indicate important roles for estrogen receptor (ER) agonists in protecting the central nervous system (CNS) from noxious consequences of neuroinflammation and neurodegeneration. Neurodegenerative processes in several CNS disorders including spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD) are assocd. with activation of microglia and astrocytes, which drive the resident neuroinflammatory response. During neurodegenerative processes, activated microglia and astrocytes cause deleterious effects on surrounding neurons. The inhibitory activity of ER agonists on microglia activation might be a beneficial therapeutic option for delaying the onset or progression of neurodegenerative injuries and diseases. Recent studies suggest that ER agonists can provide neuroprotection by modulation of cell survival mechanisms, synaptic reorganization, regenerative responses to axonal injury, and neurogenesis process. The anti-inflammatory and neuroprotective actions of ER agonists are mediated mainly via two ERs known as ERα and ERβ. Although some studies have suggested that ER agonists may be deleterious to some neuronal populations, the potential clin. benefits of ER agonists for augmenting cognitive function may triumph over the assocd. side effects. Also, understanding the modulatory activities of ER agonists on inflammatory pathways will possibly lead to the development of selective anti-inflammatory mols. with neuroprotective roles in different CNS disorders such as SCI, MS, PD, and AD in humans. Future studies should be concd. on finding the most plausible mol. pathways for enhancing protective functions of ER agonists in treating neuroinflammatory and neurodegenerative injuries and diseases in the CNS.
- 454Pike, C. J.; Carroll, J. C.; Rosario, E. R.; Barron, A. M. Protective Actions of Sex Steroid Hormones in Alzheimer’s Disease. Frontiers in Neuroendocrinology 2009, 30 (2), 239– 258, DOI: 10.1016/j.yfrne.2009.04.015[Crossref], [PubMed], [CAS], Google Scholar461https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnsV2rsbw%253D&md5=72830b36e50e6132298ed4e8c9954125Protective actions of sex steroid hormones in Alzheimer's diseasePike, Christian J.; Carroll, Jenna C.; Rosario, Emily R.; Barron, Anna M.Frontiers in Neuroendocrinology (2009), 30 (2), 239-258CODEN: FNEDA7; ISSN:0091-3022. (Elsevier B. V.)A review. Risk for Alzheimer's disease (AD) is assocd. with age-related loss of sex steroid hormones in both women and men. In post-menopausal women, the precipitous depletion of estrogens and progestogens is hypothesized to increase susceptibility to AD pathogenesis, a concept largely supported by epidemiol. evidence but refuted by some clin. findings. Exptl. evidence suggests that estrogens have numerous neuroprotective actions relevant to prevention of AD, in particular promotion of neuron viability and redn. of β-amyloid accumulation, a crit. factor in the initiation and progression of AD. Recent findings suggest neural responsiveness to estrogen can diminish with age, reducing neuroprotective actions of estrogen and, consequently, potentially limiting the utility of hormone therapies in aged women. In addn., estrogen neuroprotective actions are also modulated by progestogens. Specifically, continuous progestogen exposure is assocd. with inhibition of estrogen actions whereas cyclic delivery of progestogens may enhance neural benefits of estrogen. In recent years, emerging literature has begun to elucidate a parallel relationship of sex steroid hormones and AD risk in men. Normal age-related testosterone loss in men is assocd. with increased risk to several diseases including AD. Like estrogen, testosterone has been established as an endogenous neuroprotective factor that not only increases neuronal resilience against AD-related insults, but also reduces β-amyloid accumulation. Androgen neuroprotective effects are mediated both directly by activation of androgen pathways and indirectly by aromatization to estradiol and initiation of protective estrogen signaling mechanisms. The successful use of hormone therapies in aging men and women to delay, prevent, and or treat AD will require addnl. research to optimize key parameters of hormone therapy and may benefit from the continuing development of selective estrogen and androgen receptor modulators.
- 455Boada, M.; Antunez, C.; López-Arrieta, J.; Caruz, A.; Moreno-Rey, C.; Ramírez-Lorca, R.; Morón, F. J.; Hernández, I.; Mauleón, A.; Rosende-Roca, M.; Martínez-Lage, P.; Marín, J.; Tárraga, L.; Alegret, M.; Pedrajas, J. R.; Urda, N.; Royo, J. L.; Saez, M. E.; Gayán, J.; González-Pérez, A.; Real, L. M.; Ruiz, A.; Galán, J. J. Estrogen Receptor Alpha Gene Variants Are Associated with Alzheimer’s Disease. Neurobiol. Aging 2012, 33 (1), 198.e15– 198.e24, DOI: 10.1016/j.neurobiolaging.2010.06.016
- 456Goodman, Y.; Bruce, A. J.; Cheng, B.; Mattson, M. P. Estrogens Attenuate and Corticosterone Exacerbates Excitotoxicity, Oxidative Injury, and Amyloid β-Peptide Toxicity in Hippocampal Neurons. J. Neurochem. 1996, 66 (5), 1836– 1844, DOI: 10.1046/j.1471-4159.1996.66051836.x[Crossref], [PubMed], [CAS], Google Scholar463https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XisVSkurs%253D&md5=e78a114c34218cf81c2808c41886c157Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neuronsGoodman, Yadong; Bruce, Annadora J.; Cheng, Bin; Mattson, Mark P.Journal of Neurochemistry (1996), 66 (5), 1836-44CODEN: JONRA9; ISSN:0022-3042. (Lippincott-Raven)Steroid hormones, particularly estrogens and glucocorticoids, may play roles in the pathogenesis of neurodegenerative disorders, but their mechanisms of action are not known. We report that estrogens protect cultured hippocampal neurons against glutamate toxicity, glucose deprivation, FeSO4 toxicity, and amyloid β-peptide (Aβ) toxicity. The toxicity of each insult was significantly attenuated in cultures pretreated for 2 h with 100 nM-10 μM 17β-estradiol, estriol, or progesterone. In contrast, corticosterone exacerbated neuronal injury induced by glutamate, FeSO4, and Aβ. Several other steroids, including testosterone, aldosterone, and vitamin D, had no effect on neuronal vulnerability to the different insults. The protective actions of estrogens and progesterone were not blocked by actinomycin D or cycloheximide. Lipid peroxidn. induced by FeSO4 and Aβ was significantly attenuated in neurons and isolated membranes pretreated with estrogens and progesterone, suggesting that these steroids possess antioxidant activities. Estrogens and progesterone also attenuated Aβ- and glutamate-induced elevation of intracellular free Ca2+ concns. We conclude that estrogens, progesterone, and corticosterone can directly affect neuronal vulnerability to excitotoxic, metabolic, and oxidative insults, suggesting roles for these steroids in several different neurodegenerative disorders.
- 457Green, P. S.; Gridley, K. E.; Simpkins, J. W. Estradiol Protects against β-Amyloid (25–35)-Induced Toxicity in SK-N-SH Human Neuroblastoma Cells. Neurosci. Lett. 1996, 218 (3), 165– 168, DOI: 10.1016/S0304-3940(96)13148-7[Crossref], [PubMed], [CAS], Google Scholar464https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xnt1Ohsrw%253D&md5=49d37d6f03ba0c70aec07c67bf46de0eEstradiol protects against β-amyloid (25-35)-induced toxicity in SK-N-SH human neuroblastoma cellsGreen, Pattie S.; Gridley, Kelly E.; Simpkins, James W.Neuroscience Letters (1996), 218 (3), 165-168CODEN: NELED5; ISSN:0304-3940. (Elsevier)Estrogen-replacement therapy has been assocd. with a reduced incidence of Alzheimer's disease (AD) and improved cognition in several small open clin. trials. We assessed the possibility that estrogens may reduce toxicity of β-amyloid (Aβ) by testing the effects of β-estradiol on the toxicity of the neurotoxic fragment of β-amyloid (Aβ 25-35) in SK-N-SH neuroblastoma cells. Aβ 25-35 caused a dose-dependent death in SK-N-SH cells with a LD50 of 28.9 μM. In cultures simultaneously exposed to 20 μM Aβ and 17 β-estradiol (2 nM), Aβ-induced toxicity was reduced by 83 and 51% in two sep. studies. Further studies show that 0.2 nM 17β-estradiol was as effective as the 2 nM concn. 17α-Estradiol (2 nM) conferred neuroprotection equiv. to that of 17β-estradiol. These data support the hypothesis that estrogens reduce β-amyloid toxicity and this may help explain the beneficial effects of estrogens in AD.
- 458Behl, C.; Widmann, M.; Trapp, T.; Holsboer, F. 17-β Estradiol Protects Neurons from Oxidative Stress-Induced Cell Death in Vitro. Biochem. Biophys. Res. Commun. 1995, 216 (2), 473– 482, DOI: 10.1006/bbrc.1995.2647[Crossref], [PubMed], [CAS], Google Scholar465https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXptlentLY%253D&md5=5e63822d03088d13f78a3781649a232017β-Estradiol protects neurons from oxidative stress-induced cell death in vitroBehl, Christian; Widmann, Martina; Trapp, Thorsten; Holsboer, FlorianBiochemical and Biophysical Research Communications (1995), 216 (2), 473-82CODEN: BBRCA9; ISSN:0006-291X. (Academic)The potential antioxidant activity of 17-β estradiol and other steroid hormones in neuronal cells was investigated by studying oxidative stress-induced cell death caused by the neurotoxins amyloid β protein, hydrogen peroxide and glutamate in the clonal mouse hippocampal cell line HT22. Preincubation of the cells with 10-5 M 17-β estradiol prior to addn. of the neurotoxins prevented oxidative stress-induced cell damage and ultimately cell death, as detected with cell viability (MTT) and cell lysis (trypan blue exclusion/cell counting; propidium iodide staining) assays. At the DNA level, 17-β estradiol blocked the DNA degrdn. caused by glutamate. Other steroid hormones, such as progesterone, aldosterone, corticosterone and the steroid precursor cholesterol, did not protect the cells. The neuronal protection afforded by 17-β estradiol was estrogen receptor-independent. These data demonstrate a potent neuroprotective activity of the antioxidant 17-β estradiol, which may have implications for the prevention and treatment of Alzheimer's disease.
- 459Singer, C. A.; Rogers, K. L.; Strickland, T. M.; Dorsa, D. M. Estrogen Protects Primary Cortical Neurons from Glutamate Toxicity. Neurosci. Lett. 1996, 212 (1), 13– 16, DOI: 10.1016/0304-3940(96)12760-9[Crossref], [PubMed], [CAS], Google Scholar466https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XktlSitLk%253D&md5=a80f396129180325016450a9513e7a56Estrogen protects primary cortical neurons from glutamate toxicitySinger, Cherie A.; Rogers, Keith L.; Strickland, Tamara M.; Dorsa, Daniel M.Neuroscience Letters (1996), 212 (1), 13-16CODEN: NELED5; ISSN:0304-3940. (Elsevier)The gonadal steroid estrogen has been shown to affect neuronal growth, differentiation and survival. We examd. the ability of estrogen to protect primary cortical neurons from toxicity induced by the excitatory neurotransmitter glutamate. In these expts., a 24-h pretreatment with 15 and 50 nM 17β-estradiol significantly reduced cellular lactate dehydrogenase (LDH) release from primary cortical neurons, indicating that neurons treated with 17β-estradiol were protected from a toxic glutamate exposure. Pretreatment with related steroids such as progesterone, dihydrotestosterone, dexamethasone or cholesterol did not significantly decrease LDH release. The anti-estrogen tamoxifen blocked the protective effects of 17β-estradiol suggesting that a classical steroid hormone receptor may be involved in the mechanism subserving estrogen neuroprotection during glutamate toxicity.
- 460Zhang, Q.-G.; Raz, L.; Wang, R.; Han, D.; De Sevilla, L.; Yang, F.; Vadlamudi, R. K.; Brann, D. W. Estrogen Attenuates Ischemic Oxidative Damage Via an Estrogen Receptor α-Mediated Inhibition of NADPH Oxidase Activation. J. Neurosci. 2009, 29 (44), 13823– 13836, DOI: 10.1523/JNEUROSCI.3574-09.2009[Crossref], [PubMed], [CAS], Google Scholar467https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVSmsbjN&md5=e72641ec196dc6316e6c55f1b7713ae0Estrogen attenuates ischemic oxidative damage via an estrogen receptor α-mediated inhibition of NADPH oxidase activationZhang, Quan-Guang; Raz, Limor; Wang, Ruimin; Han, Dong; De Sevilla, Liesl; Yang, Fang; Vadlamudi, Ratna K.; Brann, Darrell W.Journal of Neuroscience (2009), 29 (44), 13823-13836CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)The goal of this study was to elucidate the mechanisms of 17β-estradiol (E2) antioxidant and neuroprotective actions in stroke. The results reveal a novel extranuclear receptor-mediated antioxidant mechanism for E2 during stroke, as well as a hypersensitivity of the CA3/CA4 region to ischemic injury after prolonged hypoestrogenicity. E2 neuroprotection was shown to involve a profound attenuation of NADPH oxidase activation and superoxide prodn. in hippocampal CA1 pyramidal neurons after stroke, an effect mediated by extranuclear estrogen receptor α (ERα)-mediated nongenomic signaling, involving Akt activation and subsequent phosphorylation/inactivation of Rac1, a factor crit. for activation of NOX2 NADPH oxidase. Intriguingly, E2 nongenomic signaling, antioxidant action, and neuroprotection in the CA1 region were lost after long-term E2 deprivation, and this loss was tissue specific because the uterus remained responsive to E2. Correspondingly, a remarkable loss of ERα, but not ERβ, was obsd. in the CA1 after long-term E2 deprivation, with no change obsd. in the uterus. As a whole, the study reveals a novel, membrane-mediated antioxidant mechanism in neurons by E2 provides support and mechanistic insights for a "crit. period" of E2 replacement in the hippocampus and demonstrates a heretofore unknown hypersensitivity of the CA3/CA4 to ischemic injury after prolonged hypoestrogenicity.
- 461Spampinato, S. F.; Molinaro, G.; Merlo, S.; Iacovelli, L.; Caraci, F.; Battaglia, G.; Nicoletti, F.; Bruno, V.; Sortino, M. A. Estrogen Receptors and Type 1 Metabotropic Glutamate Receptors Are Interdependent in Protecting Cortical Neurons against β-Amyloid Toxicity. Mol. Pharmacol. 2012, 81 (1), 12– 20, DOI: 10.1124/mol.111.074021[Crossref], [PubMed], [CAS], Google Scholar468https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtVSktro%253D&md5=752d10d11565e583471f5b1595bf19d9Estrogen receptors and type 1 metabotropic glutamate receptors are interdependent in protecting cortical neurons against β-amyloid toxicitySpampinato, Simona Federica; Molinaro, Gemma; Merlo, Sara; Iacovelli, Luisa; Caraci, Filippo; Battaglia, Giuseppe; Nicoletti, Ferdinando; Bruno, Valeria; Sortino, Maria AngelaMolecular Pharmacology (2012), 81 (1), 12-20CODEN: MOPMA3; ISSN:1521-0111. (American Society for Pharmacology and Experimental Therapeutics)We examd. the interaction between estrogen receptors (ERs) and type 1 metabotropic glutamate receptors (mGlu1 receptors) in mechanisms of neurodegeneration/neuroprotection using mixed cultures of cortical cells challenged with β-amyloid peptide. Both receptors were present in neurons, whereas only ERα but not mGlu1 receptors were found in astrocytes. Addn. of 17β-estradiol (17βE2) protected cultured neurons against amyloid toxicity, and its action was mimicked by the selective ERα agonist, 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) as well as by a cell-impermeable bovine serum albumin conjugate of 17βE2. The selective ERβ agonist, diarylpropionitrile (DPN), was only slightly neuroprotective. The mGlu1/5 receptor agonist, 3,5-dihydroxyphenylglycine (DHPG), was also neuroprotective against amyloid toxicity, and its action was abolished by the mGlu1 receptor antagonist, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ 16259685). Neuroprotection by 17βE2 or PPT (but not DPN) and DHPG was less than additive, suggesting that ERα and mGlu1 receptors activate the same pathway of cell survival. More important, neuroprotection by 17βE2 was abolished not only by the ER antagonist fulvestrant (ICI 182,780) but also by JNJ 16259685, and neuroprotection by DHPG was abolished by ICI 182,780. ERα and mGlu1 receptors were also interdependent in activating the phosphatidylinositol-3-kinase pathway, and pharmacol. blockade of this pathway abolished neuroprotection by 17βE2, DHPG, or their combination. These data provide the first evidence that ERα and mGlu1 receptors critically interact in promoting neuroprotection, information that should be taken into account when the impact of estrogen on neurodegeneration assocd. with central nervous system disorders is examd.
- 462Pike, C. J. Estrogen Modulates Neuronal Bcl-XL Expression and β-Amyloid-Induced Apoptosis: Relevance to Alzheimer’s Disease. J. Neurochem. 1999, 72 (4), 1552– 1563, DOI: 10.1046/j.1471-4159.1999.721552.x[Crossref], [PubMed], [CAS], Google Scholar469https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXitFCksLY%253D&md5=817658b7548f99e9a6ce3e079ce94d1bEstrogen modulates neuronal Bcl-XL expression and β-amyloid-induced apoptosis: relevance to Alzheimer's diseasePike, Christian J.Journal of Neurochemistry (1999), 72 (4), 1552-1563CODEN: JONRA9; ISSN:0022-3042. (Lippincott Williams & Wilkins)Recent findings indicate that estrogen is neuroprotective, a cellular effect that may contribute to its clin. benefits in delaying the development of Alzheimer's disease. The authors identify a novel neuronal action of estrogen that may contribute to its neuroprotective mechanism(s). Specifically, the authors report that estrogen significantly increases the expression of the anti-apoptotic protein Bcl-xL in cultured hippocampal neurons. This effect presumably reflects classic estrogen transcriptional regulation, as the authors identified a putative estrogen response element in the bcl-x gene. Estrogen-induced enhancement of Bcl-xL is assocd. with a redn. in measures of β-amyloid-induced apoptosis, including inhibition of both caspase-mediated proteolysis and neurotoxicity. A similar relationship between estrogen, Bcl-xL expression, and resistance to degeneration was also obsd. in human hippocampus. The authors report neuronal colocalization of estrogen receptor and Bcl-xL immunoreactivities that is most prominent in hippocampal subfield CA3, a region that shows relatively little immunoreactivity to paired helical filament-1, a marker of Alzheimer's disease neurodegeneration. These data suggest a novel mechanism of estrogen neuroprotection that may be relevant to estrogen's suggested ability to modulate neuronal viability across the life span, from neural sexual differentiation and development through age-related neurodegenerative conditions.
- 463Yao, M.; Nguyen, T.-V. V.; Pike, C. J. Estrogen Regulates Bcl-w and Bim Expression: Role in Protection against β-Amyloid Peptide-Induced Neuronal Death. J. Neurosci. 2007, 27 (6), 1422– 1433, DOI: 10.1523/JNEUROSCI.2382-06.2007[Crossref], [PubMed], [CAS], Google Scholar470https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhvFCrurY%253D&md5=c7b0ec00e418580d5f5718618cdbc4efEstrogen regulates Bcl-w and bim expression: role in protection against β-amyloid peptide-induced neuronal deathYao, Mingzhong; Nguyen, Thuy-Vi V.; Pike, Christian J.Journal of Neuroscience (2007), 27 (6), 1422-1433CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Estrogen is neuroprotective against a variety of insults, including β-amyloid peptide (Aβ); however, the underlying mechanism(s) is not fully understood. Here, we report that 17β-estradiol (E2) selectively regulates neuronal expression of the Bcl-2 family (bcl-2, bcl-x, bcl-w, bax, bak, bad, bik, bnip3, bid, and bim). In primary cerebrocortical neuron cultures under basal conditions, we observe that E2 upregulates expression of antiapoptotic Bcl-w and downregulates expression of proapoptotic Bim in an estrogen receptor (ER)-dependent manner. In the presence of toxic levels of Aβ, we observe that E2 attenuates indexes of neuronal apoptosis: c-Jun N-terminal kinase (JNK)-dependent downregulation of Bcl-w and upregulation of Bim, mitochondrial release of cytochrome c and Smac, and cell death. These neuroprotective effects of E2 against Aβ-induced apoptosis are mimicked by the JNK inhibitor SP 600125. In addn., E2 attenuates Aβ-induced JNK phosphorylation in an ER-dependent manner, but does not affect basal levels of JNK phosphorylation. These results suggest that E2 may reduce Aβ-induced neuronal apoptosis at least in part by two complementary pathways: (1) ER-dependent, JNK-independent upregulation of Bcl-w and downregulation of Bim under basal conditions, and (2) ER-dependent inhibition of Aβ-induced JNK activation and subsequent JNK-dependent downregulation of Bcl-w and upregulation of Bim, resulting in mitochondrial release of cytochrome c and Smac and eventual cell death. These data provide new understanding into the mechanisms contributing to estrogen neuroprotection, a neural function with potential therapeutic relevance to Alzheimer's disease.
- 464Zhao, L.; Wu, T.-W.; Brinton, R. D. Estrogen Receptor Subtypes Alpha and Beta Contribute to Neuroprotection and Increased Bcl-2 Expression in Primary Hippocampal Neurons. Brain Res. 2004, 1010 (1–2), 22– 34, DOI: 10.1016/j.brainres.2004.02.066[Crossref], [PubMed], [CAS], Google Scholar471https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjs1Wltbw%253D&md5=ff6963cb0c1aa4be3107225d24959c67Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neuronsZhao, Liqin; Wu, Tzu-wei; Brinton, Roberta DiazBrain Research (2004), 1010 (1,2), 22-34CODEN: BRREAP; ISSN:0006-8993. (Elsevier Science B.V.)Estrogen receptor (ER) mediated neuroprotection has been demonstrated in both in vitro and in vivo model systems. However, the relative contribution by either ER subtype, ERα or ERβ, to estrogen-induced neuroprotection remains unresolved. To address this question, the authors investigated the impact of selective ER agonists for either ERα, PPT, or ERβ, DPN, to prevent neurodegeneration in cultured hippocampal neurons exposed to excitotoxic glutamate. Using three indicators of neuronal viability and survival, the authors demonstrated that both the ERα selective agonist PPT and the ERβ selective agonist DPN protected hippocampal neurons against glutamate-induced cell death in a dose-dependent manner, with the maximal response occurring at 100 pM. Further analyses showed that both PPT and DPN enhanced Bcl-2 expression in hippocampal neurons, with an efficacy comparable to their neuroprotective capacity. Collectively, the present data indicate that activation of either ERα or ERβ can promote neuroprotection in hippocampal neurons, suggesting that both receptor subtypes could be involved in estrogen neuroprotection. As ERβ is highly expressed in the brain and has little or no expression in the breast or uterus, discovery and design of ERβ selective mols. could provide a strategy for activating the beneficial effects of estrogen in the brain without activating untoward effects of estrogen in reproductive organs.
- 465Suwanna, N.; Thangnipon, W.; Soi-ampornkul, R. Neuroprotective Effects of Diarylpropionitrile against β-Amyloid Peptide-Induced Neurotoxicity in Rat Cultured Cortical Neurons. Neurosci. Lett. 2014, 578, 44– 49, DOI: 10.1016/j.neulet.2014.06.029[Crossref], [PubMed], [CAS], Google Scholar472https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Kltb%252FE&md5=b12717240552572671b8c2de25358a6bNeuroprotective effects of diarylpropionitrile against β-amyloid peptide-induced neurotoxicity in rat cultured cortical neuronsSuwanna, Nirut; Thangnipon, Wipawan; Soi-ampornkul, RungtipNeuroscience Letters (2014), 578 (), 44-49CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Alzheimer's disease is a major cause of dementia in the elderly that involves a β-amyloid peptide (Aβ)-induced cascade of an increase in oxidative damage and inflammation. The present study demonstrated the neuroprotective effects of diarylpropionitrile (DPN), a non-steroidal estrogen receptor β selective ligand, against 10 μM Aβ1-42-induced oxidative stress and inflammation in primary rat cortical cell culture. Pre-treatment with 1-100 nM DPN significantly decreased neuronal cell death by increasing cell viability through a significant attenuation in the reactive oxygen species level, downregulation of pro-apoptotic activated caspase-3 and Bax, and upregulation of anti-apoptotic Bcl-2, thereby mitigating apoptotic morphol. alterations. DPN pre-treatment decreased the expression levels of pro-inflammatory cytokines IL-1β and IL-6 through attenuation of Aβ1-42-induced phosphorylation of mitogen-activated protein kinases JNK and p38. In addn., DPN enhanced ERK1/2 and Akt phosphorylation depressed by Aβ1-42. These findings suggest that DPN protects neurons from Aβ1-42-induced neurotoxicity through a variety of mechanisms, ranging from anti-oxidn., anti-apoptosis, through to anti-inflammation.
- 466Mateos, L.; Persson, T.; Kathozi, S.; Gil-Bea, F. J.; Cedazo-Minguez, A. Estrogen Protects against Amyloid-β Toxicity by Estrogen Receptor α-Mediated Inhibition of Daxx Translocation. Neurosci. Lett. 2012, 506 (2), 245– 250, DOI: 10.1016/j.neulet.2011.11.016[Crossref], [PubMed], [CAS], Google Scholar473https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlOkuw%253D%253D&md5=49eb420a010d6800be9d7bfe8e45dacbEstrogen protects against amyloid-β toxicity by estrogen receptor α-mediated inhibition of Daxx translocationMateos, Laura; Persson, Torbjoern; Katoozi, Shirin; Gil-Bea, Francisco Javier; Cedazo-Minguez, AngelNeuroscience Letters (2012), 506 (2), 245-250CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)Estrogen was shown to promote neuronal survival against several neurotoxic insults including β-amyloid (Aβ). The proposed mechanism includes the activation of the mitogen activated protein kinase/extracellular signal-regulated kinase (Mapk/Erk), phosphatidylinositol 3-kinase/Akt pathways and the upregulation of antiapoptotic proteins. On the other hand, Aβ neurotoxicity depends on the activation of apoptosis signal-regulating kinase 1 (Ask1), and both Ask1 activity and Aβ toxicity are inhibited by thioredoxin-1 (Trx1). Here, we explored the possibility that estrogen could protect cells against Aβ(1-42) toxicity by inhibiting the Ask1 cascade or by modulating Trx1. Cytosolic translocation of death-assocd. protein Daxx was used as indicator of Ask1 activity. Using human SH-SY5Y neuroblastoma cells, 17β-estradiol (E2) and specific agonists for estrogen receptor (ER) α or β we demonstrated that nM concns. of E2 protected against Aβ(1-42) by a mechanism depending upon ERα stimulation, Akt activation and Ask1 inhibition. Moreover, this protection would occur independently of ERβ and the induction of Trx1 expression. Our results emphasize the importance of Ask1 cascade in Aβ toxicity, and of ERα and Ask1 as targets for developing new neuroprotective drugs.
- 467Witty, C. F.; Gardella, L. P.; Perez, M. C.; Daniel, J. M. Short-Term Estradiol Administration in Aging Ovariectomized Rats Provides Lasting Benefits for Memory and the Hippocampus: A Role for Insulin-like Growth Factor-I. Endocrinology 2013, 154 (2), 842– 852, DOI: 10.1210/en.2012-1698[Crossref], [PubMed], [CAS], Google Scholar474https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitVehtL0%253D&md5=087bda417de535ad79bb2ece0eb345daShort-term estradiol administration in aging ovariectomized rats provides lasting benefits for memory and the hippocampus: a role for insulin-like growth factor-IWitty, Christine F.; Gardella, Layne P.; Perez, Maria C.; Daniel, Jill M.Endocrinology (2013), 154 (2), 842-852CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)The authors previously demonstrated that aged ovariectomized rats that had received prior estradiol treatment in middle age exhibited enhanced spatial memory and increased levels of estrogen receptor (ER)-α in the hippocampus long after estradiol treatment was terminated. The implication for cognition of increased levels of ERα resulting from prior estradiol exposure is unknown. In the absence of estrogens, growth factors, including IGF-I, can induce ERα-mediated transcription through ligand-independent mechanisms. The authors' current goal was to det. whether IGF-I mediates the ability of short-term exposure to estradiol to exert long-term effects on cognition and the hippocampus of aging females. Ovariectomized middle-aged rats were implanted with estradiol or cholesterol vehicle capsules. After 40 days, all capsules were removed and drug treatments were initiated. Half of each hormone treatment group received chronic intracerebroventricular delivery of the IGF-I receptor antagonist JB1, and the other half received artificial cerebrospinal fluid vehicle. Rats were tested on a spatial memory radial-arm maze task and hippocampi were immunostained for proteins of interest by Western blotting. As expected, previous treatment with estradiol enhanced spatial memory and increased levels of ERα in the hippocampus. JB1 reversed these effects. Previous treatment with estradiol resulted in lasting increases in levels of IGF-I receptors and phosphorylation of ERK/MAPK, a downstream signaling mol. of both ERα and IGF-I receptors, and increased levels of the ERα-regulated protein, choline acetyltransferase. JB1 blocked effects on ERK/MAPK and choline acetyltransferase. Results indicate that activation of IGF-I receptors is necessary for prior estradiol exposure to exert lasting impact on the hippocampus and memory.
- 468Azcoitia, I.; Sierra, A.; Garcia-Segura, L. M. Neuroprotective Effects of Estradiol in the Adult Rat Hippocampus: Interaction with Insulin-like Growth Factor-I Signalling. J. Neurosci. Res. 1999, 58 (6), 815– 822, DOI: 10.1002/(SICI)1097-4547(19991215)58:6<815::AID-JNR8>3.0.CO;2-R[Crossref], [PubMed], [CAS], Google Scholar475https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXnvF2gs7Y%253D&md5=98ad29ca2408a8ee569b67f47a0ad673Neuroprotective effects of estradiol in the adult rat hippocampus: interaction with insulin-like growth factor-I signalingAzcoitia, Inigo; Sierra, Amanda; Garcia-Segura, Luis M.Journal of Neuroscience Research (1999), 58 (6), 815-822CODEN: JNREDK; ISSN:0360-4012. (Wiley-Liss, Inc.)We have previously shown that 17-β-estradiol protects neurons in the dentate gyrus from kainic acid-induced death in vivo. To analyze whether this effect is mediated through estrogen receptors and through cross-talk between steroid and insulin-like growth factor (IGF) systems, we have concomitantly administered antagonists of estrogen receptor (ICI 182780) or the IGF-I receptor (JB 1) with estradiol. In addn., we have also administered IGF-I with or without the estrogen receptor antagonist. JB 1 (20 μg/mL), ICI 182780 (10-7 M), and IGF-I (100 μg/mL) were delivered into the left lateral ventricle of young ovariectomized rats via an Alzet osmotic minipump (0.5 μL/h) for 2 wk. All rats received kainic acid (7 mg/kg) or vehicle i.p. injections at day 7 after minipump implant. Also on day 7, rats treated i.c.v. with only ICI 182780 or JB 1 received a single i.p. injection of 17-β-estradiol (150 μg/rat) or vehicle. On day 14 after minipump implant, the rats were killed, brains processed, and the no. of surviving hilar neurons estd. by the optical disector technique. Both IGF-I and estradiol treatments resulted in over 90% survival of hilar neurons. The neuroprotective action of estradiol was blocked by ICI 182780 and by JB 1. Furthermore, IGF-I enhancement of neuronal survival was significantly reduced by ICI 182780. These results indicate that in this model of hippocampal lesion, the neuroprotective effect of estradiol depends both on estrogen receptors and IGF-I receptors, while the protection exerted by IGF-I depends also on estrogen receptors. In conclusion, an interaction of estrogen receptor and IGF-I receptor signaling may mediate neuroprotection in the adult rat hippocampus.
- 469Rosario, E. R.; Ramsden, M.; Pike, C. J. Progestins Inhibit the Neuroprotective Effects of Estrogen in Rat Hippocampus. Brain Res. 2006, 1099 (1), 206– 210, DOI: 10.1016/j.brainres.2006.03.127[Crossref], [PubMed], [CAS], Google Scholar476https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XntlWitb8%253D&md5=cf3cb4002fdd213b06f68397fb044f02Progestins inhibit the neuroprotective effects of estrogen in rat hippocampusRosario, Emily R.; Ramsden, Martin; Pike, Christian J.Brain Research (2006), 1099 (1), 206-210CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)Although estrogen has beneficial actions in brain, recent clin. trials demonstrated adverse neural effects of hormone therapy in postmenopausal women. The cause(s) of this disconnect between exptl. and clin. findings may include unanticipated effects of progestins. We report that both natural progesterone and the clin. progestin medroxyprogesterone acetate block estrogen neuroprotection. These findings underscore the need to evaluate neural actions of progestins in the rational design of hormone therapy.
- 470Carroll, J. C.; Rosario, E. R.; Pike, C. J. Progesterone Blocks Estrogen Neuroprotection from Kainate in Middle-Aged Female Rats. Neurosci. Lett. 2008, 445 (3), 229– 232, DOI: 10.1016/j.neulet.2008.09.010[Crossref], [PubMed], [CAS], Google Scholar477https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1egur3N&md5=33762b16fcc7e931252e280d3a98c727Progesterone blocks estrogen neuroprotection from kainate in middle-aged female ratsCarroll, Jenna C.; Rosario, Emily R.; Pike, Christian J.Neuroscience Letters (2008), 445 (3), 229-232CODEN: NELED5; ISSN:0304-3940. (Elsevier Ireland Ltd.)The neuroprotective effects of estrogen in young adult rodents are well established. Less well understood is how estrogen neuroprotection is affected by aging and interactions with progesterone. In this study, we investigated the effects of estrogen and continuous progesterone, both alone and in combination, on hippocampal neuron survival following kainate lesion in 14-mo-old female rats entering reproductive senescence. Our results show that ovariectomy-induced hormone depletion did not significantly affect the extent of kainate-induced neuron loss. Treatment of ovariectomized rats with estrogen significantly reduced neuron loss, however this effect was blocked by co-administration of continuous progesterone. Treatment of ovariectomized rats with progesterone alone did not significantly affect kainate toxicity. These results provide new insight into factors that regulate estrogen neuroprotection, which has important implications for hormone therapy in postmenopausal women.
- 471Kim, H.; Bang, O. Y.; Jung, M. W.; Ha, S. D.; Hong, H. S.; Huh, K.; Kim, S. U.; Mook-Jung, I. Neuroprotective Effects of Estrogen against Beta-Amyloid Toxicity Are Mediated by Estrogen Receptors in Cultured Neuronal Cells. Neurosci. Lett. 2001, 302 (1), 58– 62, DOI: 10.1016/S0304-3940(01)01659-7[Crossref], [PubMed], [CAS], Google Scholar478https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXitF2qsb4%253D&md5=24001eff6137aacb47a88ebde5731830Neuroprotective effects of estrogen against beta-amyloid toxicity are mediated by estrogen receptors in cultured neuronal cellsKim, H.; Bang, O. Y.; Jung, M. W.; Ha, S. D.; Hong, H. S.; Huh, K.; Kim, S. U.; Mook-Jung, I.Neuroscience Letters (2001), 302 (1), 58-62CODEN: NELED5; ISSN:0304-3940. (Elsevier Science Ireland Ltd.)Although estrogen is known to exert beneficial effects on Alzheimer's disease, its underlying cellular mechanisms have not been clear. In this study the authors investigated whether or not neuroprotective effects of estrogen are mediated by estrogen receptors (ERs). Treatment of estrogen (1.8 nM) reduced beta-amyloid (Aβ)-induced death of ER-expressing W4 cells. This effect of estrogen was blocked by a specific ER blocker ICI 182,780. When estrogen was added to HT22 cells, which lack functional ERs, Aβ-induced cell death was not affected. Transfection of HT22 cells with human ERα, but not ERβ, restored protective action of estrogen against Aβ. Hoechst staining revealed that estrogen protected ERα-expressing cells by blocking Aβ-induced apoptosis. These results indicate that estrogen blocks Aβ-induced cell death via ERα-dependent pathways.
- 472Benvenuti, S.; Luciani, P.; Vannelli, G. B.; Gelmini, S.; Franceschi, E.; Serio, M.; Peri, A. Estrogen and Selective Estrogen Receptor Modulators Exert Neuroprotective Effects and Stimulate the Expression of Selective Alzheimer’s Disease Indicator-1, a Recently Discovered Antiapoptotic Gene, in Human Neuroblast Long-Term Cell Cultures. J. Clin. Endocrinol. Metab. 2005, 90 (3), 1775– 1782, DOI: 10.1210/jc.2004-0066[Crossref], [PubMed], [CAS], Google Scholar479https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXisVOhtbY%253D&md5=1528c789117960e1867deb4949c10a91Estrogen and selective estrogen receptor modulators exert neuroprotective effects and stimulate the expression of selective Alzheimer's disease indicator-1, a recently discovered antiapoptotic gene, in human neuroblast long-term cell culturesBenvenuti, Susanna; Luciani, Paola; Vannelli, Gabriella Barbara; Gelmini, Stefania; Franceschi, Elisa; Serio, Mario; Peri, AlessandroJournal of Clinical Endocrinology and Metabolism (2005), 90 (3), 1775-1782CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)According to the fact that Alzheimer's disease (AD) is more common in postmenopausal women, estrogen treatment has been proposed. Exptl. studies, still mostly performed using animal models, demonstrated that estrogen exerts neuroprotective effects. We previously established neuroblast long-term cell cultures from human fetal olfactory epithelium. In the present study, we addressed the role of estrogen in these unique human cells, which express both the estrogen receptor (ER)-α and ERβ. We found that 17β-estradiol (17βE2) and the selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen exerted neuroprotective effects, which were independent of cell proliferation, by increasing resistance against β-amyloid-induced toxicity, with the exception of the highest concns. of raloxifene (10 and 100 nM). In addn., 17βE2 exposure protected from oxidative stress, reduced apoptosis, and increased the expression of the catalytic subunit of telomerase. Furthermore, we evaluated by quant. real-time RT-PCR whether estrogen/SERMs modulate the expression of the recently discovered seladin-1 (selective AD indicator-1) gene, which exerts neuroprotective effects and is down-regulated in AD-vulnerable brain regions. 17βE2 (100 pM to 100 nM) and SERMs (1 nM) significantly increased the amt. of seladin-1 mRNA. Conversely, 10 and 100 nM raloxifene reduced the expression of seladin-1. The effect of estrogen appears mainly mediated by ERα because the selective ERα agonist propylpyrazole-triol detd. a much greater increase of seladin-1 expression than the ERβ agonist diarylpropionitrile. Our results add new evidence, using human neuronal cells, for a beneficial effect of estrogen in preventing neurodegenerative diseases and suggest for the first time that seladin-1 may mediate this effect.
- 473Mize, A. L.; Young, L. J.; Alper, R. H. Uncoupling of 5-HT1A Receptors in the Brain by Estrogens: Regional Variations in Antagonism by ICI 182,780. Neuropharmacology 2003, 44 (5), 584– 591, DOI: 10.1016/S0028-3908(03)00044-3[Crossref], [PubMed], [CAS], Google Scholar480https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXisFWns7o%253D&md5=d09ce0e8ed6011af13cfcd14d87e933fUncoupling of 5-HT1A receptors in the brain by estrogens: regional variations in antagonism by ICI 182,780Mize, A. L.; Young, L. J.; Alper, R. H.Neuropharmacology (2003), 44 (5), 584-591CODEN: NEPHBW; ISSN:0028-3908. (Elsevier Science Ltd.)Previously we have shown that 17β-estradiol (in vivo and in vitro) rapidly decreases the function of serotonin1A (5-HT1A) receptors, allowing us to hypothesize that 17β-estradiol accomplished this via activation of a membrane estrogen receptor. Hippocampus and frontal cortex obtained from ovariectomized rats were incubated with 17β-estradiol or bovine serum albumin (BSA)-estradiol in the presence or absence of the estrogen receptor (ER) antagonist ICI 182,780. Membranes were prepd. to measure R(+)8-OH-DPAT-stimulated [35S]GTPγS binding (a measure of 5-HT1A receptor coupling and function). In both hippocampus and frontal cortex, 17β-estradiol and BSA-estradiol (50 nM) decreased R(+)8-OH-DPAT-stimulated [35S]GTPγS binding. ICI 182,780 blocked the effect of both the estrogens in hippocampus, but only the effect of 17β-estradiol in frontal cortex. Due to the inability of ICI 182,780 to block the effects of BSA-estradiol in frontal cortex, similar expts. were performed using the selective estrogen receptor modulator tamoxifen as the agonist. Tamoxifen (100 nM and 1 μM) decreased R(+)8-OH-DPAT-stimulated [35S]GTPγS binding. ICI 182,780 (1 μM) blocked the ability of tamoxifen to decrease 5-HT1A receptor coupling in the hippocampus, but not in the frontal cortex. Taken together, these data support the existence of a pharmacol. distinct ER in hippocampus vs. frontal cortex that might be responsible for rapid uncoupling of 5-HT1A receptors.
- 474Cordey, M.; Pike, C. J. Neuroprotective Properties of Selective Estrogen Receptor Agonists in Cultured Neurons. Brain Res. 2005, 1045 (1–2), 217– 223, DOI: 10.1016/j.brainres.2005.03.032[Crossref], [PubMed], [CAS], Google Scholar481https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXks1ansbs%253D&md5=94da6a8dc25ddbd13b53ba9eda7f927bNeuroprotective properties of selective estrogen receptor agonists in cultured neuronsCordey, Myriam; Pike, Christian J.Brain Research (2005), 1045 (1-2), 217-223CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)To investigate the role of the estrogen receptor (ER) in mediating neuroprotection, the neuroprotective profiles of selective ER agonists for ERα and ERβ, propylpyrazole triol (PPT) and 2,3-bis(4-hydroxyphenyl) proprionitrile (DPN), resp., were compared to that of 17β-estradiol and 17α-estradiol in primary neuron cultures challenged by β-amyloid toxicity. All compds. were found to be neuroprotective in an ER-dependent manner. However, protein kinase C (PKC) inhibition completely blocked the protective effects of 17β-estradiol and 17α-estradiol and significantly attenuated PPT but not DPN neuroprotection. These data indicate that estrogen-mediated neuroprotection likely involves a variety of mechanisms and that protection due to PKC activation is more likely due to ERα compared to ERβ.
- 475Fitzpatrick, J. L.; Mize, A. L.; Wade, C. B.; Harris, J. A.; Shapiro, R. A.; Dorsa, D. M. Estrogen-Mediated Neuroprotection against β-Amyloid Toxicity Requires Expression of Estrogen Receptor α or β and Activation of the MAPK Pathway. J. Neurochem. 2002, 82 (3), 674– 682, DOI: 10.1046/j.1471-4159.2002.01000.x[Crossref], [PubMed], [CAS], Google Scholar482https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xmt1ejsbo%253D&md5=fd532c3b30517e4fec0923fad7a29157Estrogen-mediated neuroprotection against β-amyloid toxicity requires expression of estrogen receptor α or β and activation of the MAPK pathwayFitzpatrick, Jennifer L.; Mize, Amy L.; Wade, Christian B.; Harris, Julie A.; Shapiro, Robert A.; Dorsa, Daniel M.Journal of Neurochemistry (2002), 82 (3), 674-682CODEN: JONRA9; ISSN:0022-3042. (Blackwell Science Ltd.)It is well documented that estrogen can activate rapid signaling pathways in a variety of cell types. These non-classical effects of estrogen have been reported to be important for cell survival after exposure to a variety of neurotoxic insults. Since direct evidence of the ability of the estrogen receptors (ERs) α and/or β to mediate such responses is lacking, the hippocampal-derived cell line HT22 was stably transfected with either ERα (HTERα) or ERβ (HTERβ). In HTERα and HTERβ cells, but not untransfected cells, an increase in ERK2 phosphorylation was measured within 15 min of 17β-estradiol treatment. The ER antagonist ICI 182780 (1 μM) and the MEK inhibitor, PD 98059 (50 μM) blocked this increase in ERK2 phosphorylation. Treatment of HT22, HTERα and HTERβ cells with the β-amyloid peptide (25-35) (10 μM) resulted in a significant decrease in cell viability. Pretreatment for 15 min with 10 nM 17β-estradiol resulted in a 50% increase in the no. of living cells in HTERα and HTERβ cells, but not in HT22 cells. Finally, ICI 182 780 and PD 98059 prevented 17β-estradiol-mediated protection. This study demonstrates that both ERα and ERβ can couple to rapid signaling events that mediate estrogen-elicited neuroprotection.
- 476Tiwari-Woodruff, S.; Morales, L. B. J.; Lee, R.; Voskuhl, R. R. Differential Neuroprotective and Antiinflammatory Effects of Estrogen Receptor (ER)α and ERβ Ligand Treatment. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (37), 14813– 14818, DOI: 10.1073/pnas.0703783104[Crossref], [PubMed], [CAS], Google Scholar483https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2srjsFeksg%253D%253D&md5=59d26af3f0e8e6d12676c16f6d15b53aDifferential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatmentTiwari-Woodruff Seema; Morales Laurie Beth J; Lee Ruri; Voskuhl Rhonda RProceedings of the National Academy of Sciences of the United States of America (2007), 104 (37), 14813-8 ISSN:0027-8424.Treatment with either estradiol or an estrogen receptor (ER)alpha ligand has been shown to be both antiinflammatory and neuroprotective in a variety of neurological disease models, but whether neuroprotective effects could be observed in the absence of an antiinflammatory effect has remained unknown. Here, we have contrasted effects of treatment with an ERalpha vs. an ERbeta ligand in experimental autoimmune encephalomyelitis, the multiple sclerosis model with a known pathogenic role for both inflammation and neurodegeneration. Clinically, ERalpha ligand treatment abrogated disease at the onset and throughout the disease course. In contrast, ERbeta ligand treatment had no effect at disease onset but promoted recovery during the chronic phase of the disease. ERalpha ligand treatment was antiinflammatory in the systemic immune system, whereas ERbeta ligand treatment was not. Also, ERalpha ligand treatment reduced CNS inflammation, whereas ERbeta ligand treatment did not. Interestingly, treatment with either the ERalpha or the ERbeta ligand was neuroprotective, as evidenced by reduced demyelination and preservation of axon numbers in white matter, as well as decreased neuronal abnormalities in gray matter. Thus, by using the ERbeta selective ligand, we have dissociated the antiinflammatory effect from the neuroprotective effect of estrogen treatment and have shown that neuroprotective effects of estrogen treatment do not necessarily depend on antiinflammatory properties. Together, these findings suggest that ERbeta ligand treatment should be explored as a potential neuroprotective strategy in multiple sclerosis and other neurodegenerative diseases, particularly because estrogen-related toxicities such as breast and uterine cancer are mediated through ERalpha.
- 477Bourque, M.; Dluzen, D. E.; Di Paolo, T. Signaling Pathways Mediating the Neuroprotective Effects of Sex Steroids and SERMs in Parkinson’s Disease. Front. Neuroendocrinol 2012, 33 (2), 169– 178, DOI: 10.1016/j.yfrne.2012.02.003[Crossref], [PubMed], [CAS], Google Scholar484https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XksFehu7w%253D&md5=956c5c7e59cf122a446039e7a7bdb900Signaling pathways mediating the neuroprotective effects of sex steroids and SERMs in Parkinson's diseaseBourque, Melanie; Dluzen, Dean E.; Di Paolo, ThereseFrontiers in Neuroendocrinology (2012), 33 (2), 169-178CODEN: FNEDA7; ISSN:0091-3022. (Elsevier Inc.)A review. Studies with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinson's disease have shown the ability of 17β-estradiol to protect the nigrostriatal dopaminergic system. This paper reviews the signaling pathways mediating the neuroprotective effect of 17β-estradiol against MPTP-induced toxicity. The mechanisms of 17β-estradiol action implicate activation of signaling pathways such as the phosphatidylinositol-3 kinase/Akt and the mitogen-activated protein kinase pathways. 17β-estradiol signaling is complex and integrates multiple interactions with signaling mols. that act to potentiate a protective effect. 17β-Estradiol signaling is mediated via estrogen receptors, including GPER1, but others receptors, such as the IGF-1 receptor, are implicated in the neuroprotective effect. Glial and neuronal crosstalk is a crit. factor in the maintenance of dopamine neuronal survival and in the neuroprotective action of 17β-estradiol. Compds. that stimulate GPER1 such as selective estrogen receptor modulators and phytoestrogens show neuroprotective activity and are alternatives to 17β-estradiol.
- 478Zhao, L.; Brinton, R. D. Estrogen Receptor α and β Differentially Regulate Intracellular Ca2+ Dynamics Leading to ERK Phosphorylation and Estrogen Neuroprotection in Hippocampal Neurons. Brain Res. 2007, 1172, 48– 59, DOI: 10.1016/j.brainres.2007.06.092[Crossref], [PubMed], [CAS], Google Scholar485https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVOlsrjL&md5=9df2819c0ddcc5d968e1334a6176ef17Estrogen receptor α and β differentially regulate intracellular Ca2+ dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neuronsZhao, Liqin; Brinton, Roberta DiazBrain Research (2007), 1172 (), 48-59CODEN: BRREAP; ISSN:0006-8993. (Elsevier Ltd.)Our previous analyses indicated that both estrogen receptor (ER) subtypes, ERα and ERβ, contribute to estrogen neuroprotection (L. Zhao, et al., 2004). In the present study, we sought to det. the underlying mechanisms by which ERα and ERβ promote neuronal function, with a focus on neuroprotection, and whether these mechanisms are consistent with a classical nuclear or membrane ER-mediated response. Results of these analyses demonstrated that both the ERα-selective agonist, PPT (100 pM), and the ERβ-selective agonist, DPN (100 pM), were effective in dynamically but differentially regulating intracellular calcium (Ca2+) signaling in hippocampal neurons. Consistent with the direct measurement of neuroprotective outcomes (L. Zhao, et al., 2004), PPT and DPN exerted comparable efficacy in attenuating excitotoxic glutamate (200 μM)-induced intracellular Ca2+ rise. In contrast, DPN was more efficacious than PPT in potentiating a physiol. concn. of glutamate (25 μM)-induced intracellular Ca2+ rise in these neurons. Further analyses revealed that both PPT and DPN increased ERK phosphorylation, however, the temporal profile and magnitude of response were unique to each mol. The presence of the L-type Ca2+ channel inhibitor, nifedipine (10 μM), partially inhibited 17β-estradiol- and PPT-induced increase in phosphorylated ERK expression, whereas it induced a complete inhibition of DPN-induced increase in ERK phosphorylation. Addnl. neuroprotective expts. demonstrated that the MAPK inhibitor, PD 98059 (5 μM), partially blocked 17β-estradiol-induced promotion of neuronal survival against excitotoxic glutamate (200 μM)-induced neurotoxicity, whereas it completely blocked both PPT- and DPN-induced neuroprotection. The presence of the nuclear ER antagonist, ICI 182780 (1 μM), not only failed to block all 3 mol.-induced neuroprotection, but coadministration of ICI 182780 and each single mol. exerted a comparable or even greater neuroprotection. Taken together, as an expansion of our previous analyses, these data indicate that both ERα and ERβ contribute to neuronal mechanisms leading to estrogen promotion of neuronal function but with unique signaling profiles. Activation of ERβ and induction of intracellular Ca2+ influx via the L-type channels appears to be more closely assocd. with estrogen promotion of memory mechanisms. However, ERα and ERβ play an equivalently important role in mediating estrogen neuroprotection, and, which is dependent upon the activation of the MAPK signaling. Further, the present analyses suggest that sep. from a classical nuclear ER-mediated response, estrogen promotes neuronal survival likely through a non-nuclear cytoplasm or membrane-assocd. ER-mediated rapid signaling cascade.
- 479Yang, L.-C.; Zhang, Q.-G.; Zhou, C.-F.; Yang, F.; Zhang, Y.-D.; Wang, R.-M.; Brann, D. W. Extranuclear Estrogen Receptors Mediate the Neuroprotective Effects of Estrogen in the Rat Hippocampus. PLoS One 2010, 5 (5), e9851, DOI: 10.1371/journal.pone.0009851
- 480Long, J.; He, P.; Shen, Y.; Li, R. New Evidence of Mitochondria Dysfunction in the Female Alzheimer’s Disease Brain: Deficiency of Estrogen Receptor-β. J. Alzheimer's Dis. 2012, 30 (3), 545– 558, DOI: 10.3233/JAD-2012-120283[Crossref], [PubMed], [CAS], Google Scholar487https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotF2mtrg%253D&md5=4ca1f8aaf2b21d7ce1f58de0cd7f1874New Evidence of Mitochondria Dysfunction in the Female Alzheimer's Disease Brain: Deficiency of Estrogen Receptor-βLong, Jiangang; He, Ping; Shen, Yong; Li, RenaJournal of Alzheimer's Disease (2012), 30 (3), 545-558CODEN: JADIF9; ISSN:1387-2877. (IOS Press)Accumulating evidence suggests that mitochondria are important targets for the actions of estrogens and studies indicated that localization of estrogen receptor β (ERβ) in neuronal mitochondrial (mtERβ) might directly affect neuronal mitochondrial function in vitro. However, it is unknown what expression levels and how important mtERβ is in the human brain, particularly in a brain with Alzheimer's disease (AD). In the present study, using rapidly autopsied human brain tissue, we found that the frontal cortices of female AD patients exhibited significantly reduced mtERβ, along with reduced mitochondrial cytochrome C oxidase activity, and increased protein carbonylation compared to that in normal controls. The correlation between mtERβ expression and mitochondrial cytochrome C oxidase activity in the female human brain is significant. To understand the possible mechanisms of mtERβ in AD-related mitochondrial dysfunction, using ERβKO mice as a model, we found that lack of ERβ enhanced brain reactive oxygen species generation and reduced mitochondrial membrane potential under Aβ peptide insult compared to brain mitochondria from wild-type control mice. Our studies, for the first time, demonstrated neuronal mtERβ expression in the human brain and the deficiency of mtERβ in the female AD brain is assocd. with the dysfunction of mitochondria. Our results from ERβKO mice demonstrated that ERβ depletion-induced mitochondrial dysfunction is mediated through increasing reactive oxygen generation and redn. of mitochondria membrane potential. These results indicate that ERβ depletion impairs mitochondrial function in mice, and redn. of brain mtERβ may significantly contribute to the mitochondrial dysfunction involved in AD pathogenesis in women.
- 481Xu, H.; Gouras, G. K.; Greenfield, J. P.; Vincent, B.; Naslund, J.; Mazzarelli, L.; Fried, G.; Jovanovic, J. N.; Seeger, M.; Relkin, N. R.; Liao, F.; Checler, F.; Buxbaum, J. D.; Chait, B. T.; Thinakaran, G.; Sisodia, S. S.; Wang, R.; Greengard, P.; Gandy, S. Estrogen Reduces Neuronal Generation of Alzheimer β-Amyloid Peptides. Nat. Med. 1998, 4 (4), 447– 451, DOI: 10.1038/nm0498-447[Crossref], [PubMed], [CAS], Google Scholar488https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXisVeltLk%253D&md5=0e71f6c4a209a69314dc9d9fde19761bEstrogen reduces neuronal generation of Alzheimer β-amyloid peptidesXu, Huaxi; Gouras, Gunnar K.; Greenfield, Jeffrey P.; Vincent, Bruno; Naslund, Jan; Mazzarelli, Louis; Fried, Gabriel; Jovanovic, Jasmina N.; Seeger, Mary; Relkin, Norman R.; Liao, Fang; Checler, Frederic; Buxbaum, Joseph D.; Chait, Brian T.; Thinakaran, Gopal.; Sisodia, Sangram S.; Wang, Rong; Greengard, Paul; Gandy, SamNature Medicine (New York) (1998), 4 (4), 447-451CODEN: NAMEFI; ISSN:1078-8956. (Nature America)Alzheimer's disease (AD) is characterized by the accumulation of cerebral plaques composed of 40- and 42-amino acid β-amyloid (Aβ) peptides, and autosomal dominant forms of AD appear to cause disease by promoting brain Aβ accumulation. Recent studies indicate that postmenopausal estrogen replacement therapy may prevent or delay the onset of AD. Here we present evidence that physiol. levels of 17β-estradiol reduce the generation of Aβ by neuroblastoma cells and by primary cultures of rat, mouse and human embryonic cerebrocortical neurons. These results suggest a mechanism by which estrogen replacement therapy can delay or prevent AD.
- 482Watters, J. J.; Campbell, J. S.; Cunningham, M. J.; Krebs, E. G.; Dorsa, D. M. Rapid MembraneEffects of Steroids in Neuroblastoma Cells: Effects of Estrogen on Mitogen Activated Protein Kinase Signalling Cascade and c-Fos Immediate Early Gene Transcription. Endocrinology 1997, 138 (9), 4030– 4033, DOI: 10.1210/endo.138.9.5489[Crossref], [PubMed], [CAS], Google Scholar489https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlsFeisbk%253D&md5=280b42414d49c193d2ff67f4ae8eae03Rapid membrane effects of steroids in neuroblastoma cells: effects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcriptionWatters, Jyoti J.; Campbell, Jean S.; Cunningham, Matthew J.; Krebs, Edwin G.; Dorsa, Daniel M.Endocrinology (1997), 138 (9), 4030-4033CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)Rapid effects of steroid hormones have been obsd. in neuronal cells for many years. The authors show here, that in the human neuroblastoma cell line SK-N-SH, the membrane impermeable conjugated 17β-estradiol (E2BSA) activates mitogen activated protein kinase kinase (MAPKK or MEK) and induces the phosphorylation and activation of both ERK-1 and ERK-2 (mitogen activated protein kinase or MAPK). Addnl., E2BSA induces the transcription of a reporter gene construct driven by the promoter of the mouse c-fos proto-oncogene. The effects of this membrane impermeable estrogen on c-fos transcription are not inhibited by the estrogen receptor antagonists Tamoxifen or ICI 182,780, further excluding the involvement of the intracellular estrogen receptor. This is also illustrated by the observation that E2BSA does not activate estrogen response element (ERE) mediated transcription. This is the first report of rapid membrane effects of 17β-estradiol on growth factor related signaling pathways in neuronal cells, and indicates a potential mechanism by which 17β-estradiol might affect the expression of genes whose promoters do not contain EREs but are responsive to factors acting through other response elements such as AP-1 and SRE sites.
- 483Manthey, D.; Heck, S.; Engert, S.; Behl, C. Estrogen Induces a Rapid Secretion of Amyloid β Precursor Protein via the Mitogen-Activated Protein Kinase Pathway. Eur. J. Biochem. 2001, 268 (15), 4285– 4291, DOI: 10.1046/j.1432-1327.2001.02346.x[Crossref], [PubMed], [CAS], Google Scholar490https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlvF2gsLs%253D&md5=6614e55f62d4e0942d356c4a782f69ceEstrogen induces a rapid secretion of amyloid β precursor protein via the mitogen-activated protein kinase pathwayManthey, Dieter; Heck, Stefanie; Engert, Stefanie; Behl, ChristianEuropean Journal of Biochemistry (2001), 268 (15), 4285-4291CODEN: EJBCAI; ISSN:0014-2956. (Blackwell Science Ltd.)The female sex hormone estrogen (17β-estradiol; E2) may function as a neurohormone and has multiple neuromodulatory functions in the brain. Its potent neuroprotective activities can be dependent and independent of estrogen receptors (ERs). In addn., E2 influences the processing of the amyloid β precursor protein (APP), one central step in the pathogenesis of Alzheimer's disease. Here, the authors show that physiol. concns. of E2 very rapidly cause an increased release of secreted nonamyloidogenic APP (sAPPα) in mouse hippocampal HT22 and human neuroblastoma SK-N-MC cells and that this effect is mediated through E2 via the phosphorylation of extracellular-regulated kinase 1 and 2 (ERK1/2), prominent members of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, the authors show that the activation of MAPK-signaling pathway and the enhancement of the sAPP release is independent of ERs and could be induced by E2 to a similar extent in neuronal cells either lacking or overexpressing a functional ER.
- 484Li, R.; Shen, Y.; Yang, L.-B.; Lue, L.-F.; Finch, C.; Rogers, J. Estrogen Enhances Uptake of Amyloid β-Protein by Microglia Derived from the Human Cortex. J. Neurochem. 2000, 75 (4), 1447– 1454, DOI: 10.1046/j.1471-4159.2000.0751447.x[Crossref], [PubMed], [CAS], Google Scholar491https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmslGltr8%253D&md5=36e25def67aea99d0149b23feb12eec2Estrogen enhances uptake of amyloid β-protein by microglia derived from the human cortexLi, Rena; Shen, Yong; Yang, Li-Bang; Lue, Lih-Fen; Finch, Caleb; Rogers, JosephJournal of Neurochemistry (2000), 75 (4), 1447-1454CODEN: JONRA9; ISSN:0022-3042. (Lippincott Williams & Wilkins)In recent years, inflammatory mechanisms have been increasingly appreciated as important steps in the pathol. of Alzheimer's disease (AD). There are two pathol. defects in AD: chronic inflammation and impaired clearance of amyloid β-peptide (Aβ). In the periphery, estrogen both increases macrophage phagocytosis and has antiinflammatory effects. If estrogen had a similar effect in the CNS, it could reverse inflammatory defects in AD. Although microglia are a key component of the immune system and help clear Aβ deposits in the AD brain, little is known about the effects of estrogen on CNS microglia. Therefore, we sought to det. the relationship between estrogen treatment and internalization of Aβ by microglia by quantifying the internalization of aggregated Aβ by human cortical microglia. Aβ uptake was found to be dose- and time-dependent in cultured microglia. Increased Aβ uptake was obsd. at 1.5 and 24 h after addn. of aggregated Aβ (50, 100, or 1,000 nM Aβ), and this uptake was enhanced by pretreatment with estrogen. The expression of estrogen receptor (ER) β (ER-β) was also up-regulated by estrogen treatment. Cells cotreated with ICI 182,780, an ER antagonist, showed significantly reduced internalization of Aβ in cultured microglia. These results indicate that microglia express an ER-β but that the effect of estrogen on enhancing clearance of Aβ may be related to the receptor-independent action of estrogen or to nonclassical ER effects of estrogen. Thus, stimulation of the ER might contribute to the therapeutic action of estrogen in the treatment of AD.
- 485Harris-White, M. E.; Chu, T.; Miller, S. A.; Simmons, M.; Teter, B.; Nash, D.; Cole, G. M.; Frautschy, S. A. Estrogen (E2) and Glucocorticoid (Gc) Effects on Microglia and Aβ Clearance in Vitro and in Vivo. Neurochem. Int. 2001, 39 (5–6), 435– 448, DOI: 10.1016/S0197-0186(01)00051-1[Crossref], [PubMed], [CAS], Google Scholar492https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXntVymu7k%253D&md5=4523557643f257c23a69f4d449aca50cEstrogen (E2) and glucocorticoid (Gc) effects on microglia and Aβ clearance in vitro and in vivoHarris-White, M. E.; Chu, T.; Miller, S. A.; Simmons, M.; Teter, B.; Nash, D.; Cole, G. M.; Frautschy, S. A.Neurochemistry International (2001), 39 (5-6), 435-448CODEN: NEUIDS; ISSN:0197-0186. (Elsevier Science Ltd.)The accumulation of fibrillar aggregates of β-amyloid (Aβ) in alzheimer's disease (AD) brain is assocd. with chronic brain inflammation. Although activated microglia (μglia) can potentially clear toxic amyloid, chronic activation may lead to excessive prodn. of neurotoxins. Recent epidemiol. and clin. data have raised questions about the use of anti-inflammatory steroids (glucocorticoids, Gcs) and estrogens for treatment or prevention of AD. Since very little is known about steroid effects on μglial interactions with amyloid, we investigated the effects of the synthetic Gc dexamethasone (DXM) and 17β-estradiol (E2) in vitro in a murine μglial-like N9 cell line on toxin prodn. and intracellular Aβ accumulation. To det. whether the steroid alterations of Aβ uptake in vitro had relevance in vivo, we examd. the effects of these steroids on Aβ accumulation and μglial responses to Aβ infused into rat brain. Our in vitro data demonstrate for the first time that Gc dose-dependently enhanced μglial Aβ accumulation and support previous work showing that E2 enhances Aβ uptake. Despite both steroids enhancing uptake, degrdn. was impeded, particularly with Gcs. Distinct differences between the two steroids were obsd. in their effect on toxin prodn. and cell viability. Gc dose-dependently increased toxicity and potentiated Aβ induction of nitric oxide, while E2 promoted cell viability and inhibited Aβ induction of nitric oxide. The steroid enhancement of μglial uptake and impedence of degrdn. obsd. in vitro were consistent with observations from in vivo studies. In the brains of Aβ-infused rats, the μglial staining in entorhinal cortex layer 3, not assocd. with Aβ deposits was increased in response to Aβ infusion and this effect was blocked by feeding rats prednisolone. In contrast, E2 enhanced μglial staining in Aβ-infused rats. Aβ-immunoreactive (ir) deposits were quant. smaller, appeared denser, and were assocd. with robust μglial responses. Despite the fact that steroid produced a smaller more focal deposit, total extd. Aβ in cortical homogenate was elevated. Together, the in vivo and in vitro data support a role for steroids in plaque compaction. Our data are also consistent with the hypothesis that although E2 is less potent than Gc in impeding Aβ degrdn., long term exposure to both steroids could reduce Aβ clearance and clin. utility. These data showing Gc potentiation of Aβ-induced μglial toxins may help explain the lack of epidemiol. correlation for AD. The failure of both steroids to accelerate Aβ degrdn. may explain their lack of efficacy for treatment of AD.
- 486Bruce-Keller, A. J.; Keeling, J. L.; Keller, J. N.; Huang, F. F.; Camondola, S.; Mattson, M. P. Antiinflammatory Effects of Estrogen on Microglial Activation. Endocrinology 2000, 141 (10), 3646– 3656, DOI: 10.1210/endo.141.10.7693[Crossref], [PubMed], [CAS], Google Scholar493https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmvVGms7c%253D&md5=d39a25263a317cb4dc49b6a133944fc4Antiinflammatory effects of estrogen on microglial activationBruce-Keller, Annadora J.; Keeling, Jonathan L.; Keller, Jeffrey N.; Huang, Feng F.; Camondola, Simonetta; Mattson, Mark P.Endocrinology (2000), 141 (10), 3646-3656CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)In the present study the effects of 17β-estradiol on microglial activation are described. Estrogen replacement therapy has been assocd. with decreased severity of age-related neurodegenerative diseases such as Alzheimer's disease, and estrogens have potent immunosuppressive properties outside of the brain. To det. the role that microglial cells might play in estrogen-mediated neuroprotection, primary rat microglia and N9 microglial cell lines were treated with increasing doses of 17β-estradiol before or during immunostimulation by lipopolysaccharide, phorbol ester, or interferon-γ. Pretreatment with 17β-estradiol, but not 17α-estradiol or progesterone, dose dependently attenuated microglial superoxide release and phagocytic activity. Addnl., 17β-estradiol attenuated increases in inducible nitric oxide synthase protein expression, but did not alter nuclear factor-κB activation. The antiinflammatory effects of 17β-estradiol were blocked by the antiestrogen ICI 182,780. Addnl., 17β-estradiol induced rapid phosphorylation of the p42/p44 mitogen-activated protein kinase (MAP kinase), and the MAP kinase inhibitor PD 98059 blocked the antiinflammatory effects of 17β-estradiol. Overall, these results suggest that estrogen receptor-dependent activation of MAP kinase is involved in estrogen-mediated antiinflammatory pathways in microglial cells. These results describe a novel mechanism by which estrogen may attenuate the progression of neurodegenerative disease and suggest new pathways for therapeutic intervention in clin. settings.
- 487George, S.; Petit, G. H.; Gouras, G. K.; Brundin, P.; Olsson, R. Nonsteroidal Selective Androgen Receptor Modulators and Selective Estrogen Receptor β Agonists Moderate Cognitive Deficits and Amyloid-β Levels in a Mouse Model of Alzheimer’s Disease. ACS Chem. Neurosci. 2013, 4 (12), 1537– 1548, DOI: 10.1021/cn400133s[ACS Full Text], [CAS], Google Scholar494https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVWjsLfM&md5=e5ed323f02b34a16e96ed326e2b59f95Nonsteroidal Selective Androgen Receptor Modulators and Selective Estrogen Receptor β Agonists Moderate Cognitive Deficits and Amyloid-β Levels in a Mouse Model of Alzheimer's DiseaseGeorge, Sonia; Petit, Geraldine H.; Gouras, Gunnar K.; Brundin, Patrik; Olsson, RogerACS Chemical Neuroscience (2013), 4 (12), 1537-1548CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Decreases of the sex steroids, testosterone and estrogen, are assocd. with increased risk of Alzheimer's disease. Testosterone and estrogen supplementation improves cognitive deficits in animal models of Alzheimer's disease. Sex hormones play a role in the regulation of amyloid-β via induction of the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme. To mimic the effect of dihydrotestosterone (DHT), the authors administered a selective androgen receptor agonist, ACP-105, alone and in combination with the selective estrogen receptor β (ERβ) agonist AC-186 to male gonadectomized triple transgenic mice. The authors assessed long-term spatial memory in the Morris water maze, spontaneous locomotion, and anxiety-like behavior in the open field and in the elevated plus maze. The authors found that ACP-105 given alone decreases anxiety-like behavior. Furthermore, when ACP-105 is administered in combination with AC-186, they increase the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme and decrease amyloid-β levels in the brain as well as improve cognition. Interestingly, the androgen receptor level in the brain was increased by chronic treatment with the same combination treatment, ACP-105 and AC-186, not seen with DHT or ACP-105 alone. Based on these results, the beneficial effect of the selective ERβ agonist as a potential therapeutic for Alzheimer's disease warrants further investigation.
- 488Yue, X.; Lu, M.; Lancaster, T.; Cao, P.; Honda, S. I.; Staufenbiel, M.; Harada, N.; Zhong, Z.; Shen, Y.; Li, R. Brain Estrogen Deficiency Accelerates Aβ Plaque Formation in an Alzheimer’s Disease Animal Model. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (52), 19198– 19203, DOI: 10.1073/pnas.0505203102[Crossref], [PubMed], [CAS], Google Scholar495https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XivV2ntQ%253D%253D&md5=32b673dfb677f2dc03b94f8b335c5f6dBrain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal modelYue, Xu; Lu, Melissa; Lancaster, Techie; Cao, Phillip; Honda, Shin-Ichiro; Staufenbiel, Matthias; Harada, Nobuhiro; Zhong, Zhenyu; Shen, Yong; Li, RenaProceedings of the National Academy of Sciences of the United States of America (2005), 102 (52), 19198-19203CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Much evidence indicates that women have a higher risk of developing Alzheimer's disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor. In rapidly acquired postmortem brains from women with AD, we found greatly reduced estrogen levels compared with those from age- and gender-matched normal control subjects; AD and control subjects had comparably low levels of serum estrogen. We examd. the onset and severity of AD pathol. assocd. with estrogen depletion by using a gene-based approach, by crossing the estrogen-synthesizing enzyme aromatase gene knockout mice with APP23 transgenic mice, a mouse model of AD, to produce estrogen-deficient APP23 mice. Compared with APP23 transgenic control mice, estrogen-deficient APP23 mice exhibited greatly reduced brain estrogen and early-onset and increased β amyloid peptide (Aβ) deposition. These mice also exhibited increased Aβ prodn., and microglia cultures prepd. from the brains of these mice were impaired in Aβ clearance/degrdn. In contrast, ovariectomized APP23 mice exhibited plaque pathol. similar to that obsd. in the APP23 transgenic control mice. Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathol.
- 489Tanzi, R. E.; Moir, R. D.; Wagner, S. L. Clearance of Alzheimer’s Aβ Peptide: The Many Roads to Perdition. Neuron 2004, 43, 605– 608, DOI: 10.1016/j.neuron.2004.08.024[Crossref], [PubMed], [CAS], Google Scholar496https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXns1ymsrg%253D&md5=57e1c038b256c85240463ca9b14afcadClearance of Alzheimer's Aβ peptide: The many roads to perditionTanzi, R. E.; Moir, R. D.; Wagner, S. L.Neuron (2004), 43 (5), 605-608CODEN: NERNET; ISSN:0896-6273. (Cell Press)A review. The amyloid hypothesis of Alzheimer's disease (AD) maintains that the accumulation of the amyloid β protein (Aβ) is a crit. event in disease pathogenesis. A great deal of both academic and com. research has focused on the mechanisms by which Aβ is generated. However, investigations into the mechanisms underlying Aβ clearance have blossomed over the last several years. This minireview will summarize pathways involved in the removal of cerebral Aβ, including enzymic degrdn. and receptor-mediated efflux out of the brain.
- 490Wei, Y.; Zhou, J.; Wu, J.; Huang, J. ERβ Promotes Aβ Degradation via the Modulation of Autophagy. Cell Death Dis. 2019, 10 (8), 565, DOI: 10.1038/s41419-019-1786-8[Crossref], [PubMed], [CAS], Google Scholar497https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MzpvFygtw%253D%253D&md5=d6dd608f094f1834fcd76478bdd7ab2dERβ promotes Aβ degradation via the modulation of autophagyWei Yong; Zhou Jiawei; Wu Jun; Huang JianCell death & disease (2019), 10 (8), 565 ISSN:.Alzheimer's Disease (AD) is the most common neurodegenerative disorder in the elderly. Beta-amyloid (Aβ) peptide accumulation is considered as a primary cause of AD pathogenesis, with defective autophagy in patients' brains. Enhanced autophagic activity has been reported to promote Aβ clearance in vitro and in vivo models. Meanwhile, there is growing evidence that estrogen receptor β (ERβ) is a viable therapeutic target that can ameliorate the pathological features associated with AD. Very little is known about the detailed molecular mechanisms underlying the relationship between ERβ, autophagy, and Aβ degradation in AD. This study aims to uncover whether ERβ participates in autophagy and promotes extracellular Aβ1-42 degradation through the autophagy-lysosome system. Here we find that overexpression of ERβ caused autophagic activation as seen by increased microtubule-associated protein 1 light chain 3-II (LC3-II), SQSTM1 (sequestosome 1) degradation, LC3 punctate distribution, autophagosome, and autolysosome accumulation. In addition, we show that ERβ could induce autophagy through direct protein-protein interaction with ATG7 (E1-like enzyme). Furthermore, ERβ-mediated decrease in Aβ1-42 was blocked by the autophagy inhibitor chloroquine (CQ) in SH-SY5Y cells and the HEK293T (AβPPsw) model. Aβ1-42 or CQ induced cytotoxicity was restored by a selective ERβ activator diarylpropionitrile (DPN). Collectively, these data indicate that overexpression of ERβ exerts a neuroprotective effect through interacting with ATG7 protein and further enhances autophagy-lysosomal activity for Aβ1-42 clearance at the cellular level.
- 491Hayes, M. T. Parkinson’s Disease and Parkinsonism. American Journal of Medicine 2019, 132 (7), 802– 807, DOI: 10.1016/j.amjmed.2019.03.001.[Crossref], [PubMed], [CAS], Google Scholar498https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cbmtVartA%253D%253D&md5=31c8a0bb44baf180225ca9aed18c4a18Parkinson's Disease and ParkinsonismHayes Michael TThe American journal of medicine (2019), 132 (7), 802-807 ISSN:.Parkinson's disease is a progressive neurodegenerative disease characterized by tremor and bradykinesia and is a common neurologic ailment. Male sex and advancing age are independent risk factors and, as the population ages, is taking an increasing toll on productivity and medical resources. There are a number of other extrapyramidal conditions that can make the diagnosis challenging. Unlike other neurodegenerative diseases, idiopathic Parkinson's disease has effective treatments that mitigate symptoms. Medications can improve day-to-day function and, in cases where medication does not give a sustained benefit or has significant side effects, treatments like deep brain stimulation result in improved quality of life.
- 492Popat, R. A.; Van Den Eeden, S. K.; Tanner, C. M.; McGuire, V.; Bernstein, A. L.; Bloch, D. A.; Leimpeter, A.; Nelson, L. M. Effect of Reproductive Factors and Postmenopausal Hormone Use on the Risk of Parkinson Disease. Neurology 2005, 65 (3), 383– 390, DOI: 10.1212/01.wnl.0000171344.87802.94[Crossref], [PubMed], [CAS], Google Scholar499https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmsVyjtLY%253D&md5=4e8bdd89034e9ea435f588a3d86c2c9cEffect of reproductive factors and postmenopausal hormone use on the risk of Parkinson diseasePopat, R. A.; Van Den Eeden, S. K.; Tanner, C. M.; McGuire, V.; Bernstein, A. L.; Bloch, D. A.; Leimpeter, A.; Nelson, L. M.Neurology (2005), 65 (3), 383-390CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: Parkinson disease (PD) is less common in women possibly because of hormonal or reproductive influences. The objective of this study was to evaluate the assocns. of reproductive factors and postmenopausal hormone use with the risk of PD among postmenopausal women. Methods: Incident cases and randomly selected age-matched controls who were members of the Kaiser Permanente Medical Care Program (KPMCP) of Northern California participated in the study conducted during the years 1994 to 1995. Statistical analyses were carried out using logistic regression. Results: The assocn. of postmenopausal hormone use with PD risk depended on the type of menopause. Among women with history of a hysterectomy with or without an oophorectomy, estrogen use alone was assocd. with a 2.6-fold increased risk (adjusted odds ratio (OR) 2.6, 95% CI: 1.1 to 6.1) and significant trends in the risk of PD were obsd. with increasing duration of estrogen use, but disease risk was not influenced by recency of use. In contrast, among women with natural menopause, no increased risk of PD was obsd. with hormone use (estrogen alone or a combined estrogen-progestin regimen). Early age at final menstrual period (44 years or younger) was assocd. with redn. in risk (adjusted OR 0.5, 95% CI: 0.3 to 1.0). Age at menarche and parity were not assocd. with the risk of PD. Conclusion: Postmenopausal use of estrogen alone may increase the risk of Parkinson disease (PD) among women with a hysterectomy. Among women with natural menopause for whom the usual treatment is combined estrogen-progestin therapy, no increased risk of PD was obsd.
- 493Wang, P.; Li, J.; Qiu, S.; Wen, H.; Du, J. Hormone Replacement Therapy and Parkinson’s Disease Risk in Women: A Meta-Analysis of 14 Observational Studies. Neuropsychiatr. Dis. Treat. 2015, 11, 59– 66, DOI: 10.2147/NDT.S69918[Crossref], [PubMed], [CAS], Google Scholar500https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mrjtlequw%253D%253D&md5=68aef7f78d6f85cee0571952bcdfbee0Hormone replacement therapy and Parkinson's disease risk in women: a meta-analysis of 14 observational studiesWang Peifu; Li Jilai; Qiu Shi; Wen Honfeng; Du JichenNeuropsychiatric disease and treatment (2015), 11 (), 59-66 ISSN:1176-6328.BACKGROUND AND PURPOSE: Published data on the relationship of hormone replacement therapy (HRT) with Parkinson's disease (PD) were inconclusive. Thus, a systematic meta-analysis of observational studies was performed to clarify this topic. METHODS: The databases of PubMed and EMBASE were searched for case-control or cohort studies published up till June 2, 2014. Meta-analysis of the relative risks (RRs) with 95% confidence intervals (CIs) was estimated using random-effects models. RESULTS: A final total of ten case-control and four cohort studies were included in our meta-analysis. The overall combined RR of PD for ever users versus never users of HRT was 1.00 (95% CI: 0.84-1.20). Limited to those subjects who only use estrogen, a similar trend was detected (RR: 0.95, 95% CI: 0.69-1.30). In the subgroup analysis by study design, no significant association was observed in case-control studies (RR: 0.79, 95% CI: 0.62-1.02), whereas a positive association was found in cohort studies (RR: 1.24, 95% CI: 1.10-1.40). In further analysis according to study quality, an inverse association was found in the low-quality group (RR: 0.58, 95% CI: 0.40-0.82), whereas a positive association was found in the high-quality group (RR: 1.16, 95% CI: 1.02-1.31). CONCLUSION: In summary, our results of meta-analysis do not support a protective role of HRT in female PD development.
- 494Currie, L. J.; Harrison, M. B.; Trugman, J. M.; Bennett, J. P.; Wooten, G. F. Postmenopausal Estrogen Use Affects Risk for Parkinson Disease. Arch. Neurol. 2004, 61 (6), 886– 888, DOI: 10.1001/archneur.61.6.886[Crossref], [PubMed], [CAS], Google Scholar501https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2czgvVSlsA%253D%253D&md5=767a64537757741e871b0e657af47625Postmenopausal estrogen use affects risk for Parkinson diseaseCurrie Lillian J; Harrison Madaline B; Trugman Joel M; Bennett James P; Wooten G FrederickArchives of neurology (2004), 61 (6), 886-8 ISSN:0003-9942.BACKGROUND: Although estrogen therapy has been associated with improved cognitive functioning, a reduced risk of dementia in women with Parkinson disease (PD), and a decreased risk of Alzheimer disease, estrogen therapy has not affected the risk of PD per se. OBJECTIVE: To determine whether postmenopausal women with PD differed from control subjects with regard to estrogen exposure.Design, Setting, and Patients A case-control design was used, abstracting questionnaire data obtained via interview from 133 female PD cases and 128 female controls during routine outpatient clinic visits in 1999 at a mid-Atlantic tertiary care referral center. There were 140 subjects (68 PD cases and 72 controls) who met the inclusion criteria. Main Outcome Measure Use of postmenopausal estrogen therapy. RESULTS: More women in the control group than in the PD group took postmenopausal estrogen (36 [50%] of 72 women vs 17 [25%] of 68 women; P<.003), and women who had taken postmenopausal estrogen were less likely to develop PD than those who had not (odds ratio, 0.40 [95% confidence interval, 0.19-0.84]; P<.02). Among PD cases only, postmenopausal estrogen use was not associated with age of onset. CONCLUSION: Postmenopausal estrogen therapy may be associated with a reduced risk of PD in women.
- 495Bourque, M.; Morissette, M.; Di Paolo, T. Repurposing Sex Steroids and Related Drugs as Potential Treatment for Parkinson’s Disease. Neuropharmacology 2019, 147, 37– 54[Crossref], [PubMed], [CAS], Google Scholar502https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXptlyrs7g%253D&md5=c84953b16b20c814ba37776792e3abc1Repurposing sex steroids and related drugs as potential treatment for Parkinson's diseaseBourque, Melanie; Morissette, Marc; Di Paolo, ThereseNeuropharmacology (2019), 147 (), 37-54CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)Parkinson's disease (PD) is a neurodegenerative disorder for which a greater prevalence and incidence is described in men. This suggests a protective effect of sex hormones in the brain. Therefore, steroids and drugs to treat endocrine conditions could have addnl. application for PD. Here, we review the protective effect of sex hormones, particularly estrogens, progesterone, androgens and dehydroepiandrosterone, in animal models of PD and also in human studies. Data also support that drugs affecting estrogen neurotransmission such as selective estrogen receptor modulators or affecting steroid metab. with 5α-reductase inhibitors could be repositioned for treatment of PD. Sex steroids are also modulator of neurotransmission, thus they could repurposed to treat PD motor symptoms and to modulate the response to PD medication. No drug is yet available to limit PD progression. PD is a complex disease implicating multiple pathol. processes and a therapeutic strategy using drugs with several mechanisms of action, such as sex steroids and endocrine drugs are interesting repositioning options for symptomatic treatment and disease-modifying activity for PD.
- 496Blanchet, P. J.; Fang, J.; Hyland, K.; Arnold, L. A.; Mouradian, M. M.; Chase, T. N. Short-Term Effects of High-Dose 17β-Estradiol in Postmenopausal PD Patients: A Crossover Study. Neurology 1999, 53 (1), 91– 95, DOI: 10.1212/WNL.53.1.91[Crossref], [PubMed], [CAS], Google Scholar503https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXkvFCktrY%253D&md5=7f31de833c5c5a6ab5035d6186560d71Short-term effects of high-dose 17β-estradiol in postmenopausal PD patients: a crossover studyBlanchet, P. J.; Fang, J.; Hyland, K.; Arnold, L. A.; Mouradian, M. M.; Chase, T. N.Neurology (1999), 53 (1), 91-95CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)A double-blind, placebo-controlled, 2-arm crossover study of high-dose transdermal 17β-estradiol was conducted in 8 postmenopausal women with mild to moderate Parkinson's disease (PD), all but one of whom exhibited levodopa-induced dyskinesias. The patients were randomized initially to receive either hormonal treatment or placebo for 2 wk, followed by a 2-wk washout period, and then another 2-wk crossover treatment period. Active treatment employed 4 skin patches, each releasing 0.1 mg estradiol daily, replaced every 2-3 days. After 10 days of treatment a redn. was obsd. in the antiparkinsonian threshold dose of i.v. levodopa. The mean duration and magnitude of the antiparkinsonian response to threshold or high doses of levodopa were unchanged, and dyskinesia scores were unaltered during 17β-estradiol treatment compared with placebo. No worsening of "on" time or motor ratings with estrogen treatment was documented. Thus, 17β-estradiol appears to display a slight prodopaminergic (or antiparkinsonian) effect without consistently altering dyskinesias. Std. postmenopausal replacement therapy with transdermal 17β-estradiol is likely to be well tolerated by many female parkinsonian patients.
- 497Strijks, E.; Kremer, J. A. M.; Horstink, M. W. I. M. Effects of Female Sex Steroids on Parkinson’s Disease in Postmenopausal Women. Clin. Neuropharmacol. 1999, 22 (2), 93– 97, DOI: 10.1097/00002826-199903000-00005[Crossref], [PubMed], [CAS], Google Scholar504https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXisFajtLs%253D&md5=a73038cd8fab8adede3a2d44a85d111eEffects of female sex steroids on Parkinson's disease in postmenopausal womenStrijks, Elma; Kremer, Jan A. M.; Horstink, Martin W. I. M.Clinical Neuropharmacology (1999), 22 (2), 93-97CODEN: CLNEDB; ISSN:0362-5664. (Lippincott Williams & Wilkins)There are conflicting reports about estrogen modulating the activity of nigrostriatal dopaminergic neurons. Furthermore, modulation may be influenced by progesterone levels. Therefore, the clin. effects of sex steroids on parkinsonian symptoms in postmenopausal women with Parkinson's disease (PD) were analyzed in the present study. Patients (n = 12) were under the age of 80, able to perform the motor function tests, and showed no contraindications for estrogen suppletion. Motor function was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) and a patient interview on subjective changes. In a placebo-controlled, randomized, double-blind trial lasting 8 wk, no significant dopaminergic effect of estradiol (E2) could be demonstrated, whereas in an open trial phase lasting 2 wk, progesterone seemed to have an antidopaminergic effect. Several mechanisms are discussed that can account for the fact that we found no effect of E2 on motor functioning in our patients with PD.
- 498Dluzen, D. E.; McDermott, J. L.; Anderson, L. I. Tamoxifen Eliminates Estrogen’s Neuroprotective Effect upon MPTP-Induced Neurotoxicity of the Nigrostriatal Dopaminergic System. Neurotoxic. Res. 2001, 3 (3), 291– 300, DOI: 10.1007/BF03033268[Crossref], [PubMed], [CAS], Google Scholar505https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXotVeku7g%253D&md5=2c6bfa6c46a6c362b7769c6e4b8d153bTamoxifen eliminates estrogen's neuroprotective effect upon MPTP-induced neurotoxicity of the nigrostriatal dopaminergic systemDluzen, Dean E.; McDermott, Janet L.; Anderson, Linda I.Neurotoxicity Research (2001), 3 (3), 291-300CODEN: NURRFI; ISSN:1029-8428. (Harwood Academic Publishers)The capacity for 17-α and 17-β estradiol to modulate MPTP-induced neurotoxicity of the nigrostriatal dopaminergic system and potential antagonism of this modulation by the anti-estrogen, tamoxifen, were evaluated. Treatment of retired breeder ovariectomized C57/BI mice with 17-β estradiol diminished the amt. of striatal dopamine redn. resulting from MPTP treatment with striatal dopamine concns. of these 17-β estradiol treated mice failing to differ significantly from vehicle treated controls. A combined administration of 17-β estradiol with tamoxifen abolished this neuroprotective effect of estrogen as striatal dopamine concns. of this group were significantly lower than vehicle treated controls. Results of 17-α estradiol were less effective since striatal dopamine concns. of these mice following MPTP treatment were significantly decreased as compared with vehicle controls. In contrast to the nigrostriatal dopaminergic system, no statistically significant effects of these treatments were obsd. upon olfactory bulb dopamine concns. Taken together, these results show that 17-β, but not an equiv. concn. of 17-α, estradiol was effective in decreasing striatal dopamine neurotoxicity to MPTP. This effect of 17-β estradiol was abolished by tamoxifen. These data have important implications regarding the mechanisms of estrogen-tamoxifen interactions within the nigrostriatal dopaminergic system as well as for clin. applications of tamoxifen within pre-menopausal women.
- 499Morissette, M.; Sweidi, S. Al; Callier, S.; Di Paolo, T. Estrogen and SERM Neuroprotection in Animal Models of Parkinson’s Disease. Mol. Cell. Endocrinol. 2008, 290 (1–2), 60– 69, DOI: 10.1016/j.mce.2008.04.008[Crossref], [PubMed], [CAS], Google Scholar506https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpsValt7Y%253D&md5=909079982647aa992148a072b8fdb1deEstrogen and SERM neuroprotection in animal models of Parkinson's diseaseMorissette, Marc; Al Sweidi, Sara; Callier, Sophie; Di Paolo, ThereseMolecular and Cellular Endocrinology (2008), 290 (1-2), 60-69CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ireland Ltd.)A review. A higher prevalence and incidence of Parkinson disease (PD) is obsd. in men and beneficial motor effects of estrogens are obsd. in parkinsonian women. Lesion of the dopamine (DA) nigrostriatal pathway in animals with 1-Me 4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) provides a model of PD and this is based on its use in humans as side-product of a drug abuse. Presently treatment of PD is mainly symptomatic. The MPTP mouse is used to study the neuroprotective roles of estrogenic drugs on the DA system. Estrogens, but not androgens, are active neuroprotectants as well as progesterone and dehydroepiandrosterone. An estrogen receptor agonist PPT and the selective estrogen receptor modulator raloxifene are also neuroprotective. Striatal DA neurons of estrogen receptor alpha knockout mice are more susceptible to MPTP toxicity than wild-type mice and neuroprotection by estradiol is assocd. with the activation of the PI3-K pathway involving Akt, GSK3β, Bcl2 and BAD.
- 500Baraka, A. M.; Korish, A. A.; Soliman, G. A.; Kamal, H. The Possible Role of Estrogen and Selective Estrogen Receptor Modulators in a Rat Model of Parkinson’s Disease. Life Sci. 2011, 88 (19–20), 879– 885, DOI: 10.1016/j.lfs.2011.03.010[Crossref], [PubMed], [CAS], Google Scholar507https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsFShurk%253D&md5=eac948c5383fbf5eb0a44efffbb54030The possible role of estrogen and selective estrogen receptor modulators in a rat model of Parkinson's diseaseBaraka, Azza M.; Korish, Aida A.; Soliman, Gehan A.; Kamal, HananLife Sciences (2011), 88 (19-20), 879-885CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)The aim of the present study was to assess and compare the effect of 17β-estradiol and two different selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, as well as a selective estrogen receptor alpha agonist, propyl-pyrazole-triol (PPT) and a selective estrogen receptor beta agonist, diarylpropionitrile (DPN), on behavioral and biochem. alterations in 6-hydroxydopamine (6-OHDA)-induced nigral dopaminergic cell death in rats. 80 Female Wister rats were used. Animals were divided into eight equal groups: Group I; Sham operated, Group II; subjected to ovariectomy (OVX), Group III; OVX rats received striatal injection of 6-OHDA, Groups IV-VIII; OVX rats received striatal injection of 6-OHDA and were injected daily with 17β-estradiol, tamoxifen, raloxifene, PPT and DPN resp. for 5 days before 6-OHDA and continued for further 2 wk. Results showed that striatal injection of 6-OHDA produced significant behavioral alteration suggestive of PD, together with significant decrease in striatal dopamine, homovanillic acid (HVA) and 3,4-dihydroxyphenyl acetic acid (DOPAC) concns. 6-OHDA-induced nigral dopaminergic cell death was characterized by oxidative stress, evidenced by significant decrease in striatal glutathione peroxidase activity, as well as apoptosis, evidenced by significant increase in nigral caspase-3 activity. Treatment with 17β-estradiol, raloxifene, PPT, but neither tamoxifen nor DPN, resulted in significant amelioration of the behavioral and biochem. alterations induced by 6-OHDA. These findings suggest that estrogen and some SERMs having estrogenic agonist activity in the brain, like raloxifene, might exert beneficial effect in PD.
- 501McFarland, K.; Price, D. L.; Davis, C. N.; Ma, J.-N.; Bonhaus, D. W.; Burstein, E. S.; Olsson, R. AC-186, a Selective Nonsteroidal Estrogen Receptor β Agonist, Shows Gender Specific Neuroprotection in a Parkinson’s Disease Rat Model. ACS Chem. Neurosci. 2013, 4 (9), 1249– 1255, DOI: 10.1021/cn400132u[ACS Full Text], [CAS], Google Scholar508https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFOqu7rF&md5=52bc40346a15593c280019ae2c8b2600AC-186, a Selective Nonsteroidal Estrogen Receptor β Agonist, Shows Gender Specific Neuroprotection in a Parkinson's Disease Rat ModelMcFarland, Krista; Price, Diana L.; Davis, Christopher N.; Ma, Jian-Nong; Bonhaus, Douglas W.; Burstein, Ethan S.; Olsson, RogerACS Chemical Neuroscience (2013), 4 (9), 1249-1255CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Drugs that selectively activate estrogen receptor β (ERβ) are potentially safer than the nonselective estrogens currently used in hormonal replacement treatments that activate both ERβ and ERα. The selective ERβ agonist AC-186 was evaluated in a rat model of Parkinson's disease induced through bilateral 6-hydroxydopamine lesions of the substantia nigra. In this model, AC-186 prevented motor, cognitive, and sensorimotor gating deficits and mitigated the loss of dopamine neurons in the substantia nigra, in males, but not in females. Furthermore, in male rats, 17β-estradiol, which activates ERβ and ERα with equal potency, did not show the same neuroprotective benefits as AC-186. Hence, in addn. to a beneficial safety profile for use in both males and females, a selective ERβ agonist has a differentiated pharmacol. profile compared to 17β-estradiol in males.
- 502Sierra, A.; Gottfried-Blackmore, A.; Milner, T. A.; McEwen, B. S.; Bulloch, K. Steroid Hormone Receptor Expression and Function in Microglia. Glia 2008, 56 (6), 659– 674, DOI: 10.1002/glia.20644[Crossref], [PubMed], [CAS], Google Scholar509https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c7os12nsA%253D%253D&md5=2537a6e7d539d13d0c282566dc0cfd3fSteroid hormone receptor expression and function in microgliaSierra Amanda; Gottfried-Blackmore Andres; Milner Teresa A; McEwen Bruce S; Bulloch KarenGlia (2008), 56 (6), 659-74 ISSN:0894-1491.Steroid hormones such as glucocorticoids and estrogens are well-known regulators of peripheral immune responses and also show anti-inflammatory properties in the brain. However, the expression of steroid hormone receptors in microglia, the pivotal immune cell that coordinates the brain inflammatory response, is still controversial. Here we use real time RT-PCR to show that microglia, isolated from adult fms-EGFP mice by FACS, express glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and estrogen receptor alpha (ERalpha). GR was the most abundant steroid hormone receptor transcript in microglia. The presence of GR and ERalpha immunoreactivity was further confirmed in vivo at the ultrastructural level. To understand the role of steroid hormone receptors during the inflammation process, we evaluated the expression of steroid hormone receptors after inflammatory challenge and found a significant down-regulation of GR, MR, and ERalpha in microglia. Finally, we tested the immunomodulatory properties of estrogens and glucocorticoids. Estradiol benzoate did not have any significant impact on the inflammatory profile of ex vivo sorted microglia, either in resting conditions or after challenge. Furthermore, corticosterone was a more consistent anti-inflammatory agent than 17beta-estradiol in vitro. Our results support the hypothesis that adult microglia are a direct target of steroid hormones and that glucocorticoids, through the predominant expression of GR and MR, are the primary steroid hormone regulators of microglial inflammatory activity. The down-regulation of steroid hormone receptors after LPS challenge may serve as a prerequisite to suppressing the anti-inflammatory actions of endogenous steroid hormones on the immune system, and contribute to a sustained activation of microglia.
- 503Barreto, G.; Santos-Galindo, M.; Diz-Chaves, Y.; Pernía, O.; Carrero, P.; Azcoitia, I.; Garcia-Segura, L. M. Selective Estrogen Receptor Modulators Decrease Reactive Astrogliosis in the Injured Brain: Effects of Aging and Prolonged Depletion of Ovarian Hormones. Endocrinology 2009, 150 (11), 5010– 5015, DOI: 10.1210/en.2009-0352[Crossref], [PubMed], [CAS], Google Scholar510https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVCht7bJ&md5=2a0b63f7371e51901b11082774430ffdSelective estrogen receptor modulators decrease reactive astrogliosis in the injured brain: effects of aging and prolonged depletion of ovarian hormonesBarreto, George; Santos-Galindo, Maria; Diz-Chaves, Yolanda; Pernia, Olga; Carrero, Paloma; Azcoitia, Inigo; Garcia-Segura, Luis M.Endocrinology (2009), 150 (11), 5010-5015CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)After brain injury, astrocytes acquire a reactive phenotype characterized by a series of morphol. and mol. modifications, including the expression of the cytoskeletal protein vimentin. Previous studies have shown that estradiol down-regulates reactive astrogliosis. In this study we assessed whether raloxifene and tamoxifen, two selective estrogen receptor modulators, have effects similar to estradiol in astrocytes. We also assessed whether aging and the timing of estrogenic therapy after ovariectomy influence the action of the estrogenic compds. Four groups of animals were studied: (1) young rats, ovariectomized at 2 mo of age; (2) middle-aged rats, ovariectomized at 8 mo of age; (3) aged rats, ovariectomized at 18 mo of age; and (4) aged rats, ovariectomized at 2 mo and sham operated at 18 mo of age. Fifteen days after ovariectomy or sham surgery, animals received a stab wound brain injury and the treatment with the estrogenic compds. The no. of vimentin-immunoreactive astrocytes after injury was significantly higher in the hippocampus of aged rats after a long-term ovariectomy compared with aged animals after a short-term ovariectomy and middle-aged rats. In addn., reactive astrocytes were more numerous in the two groups of aged animals than in young animals. Despite these differences, the estrogenic compds. reduced reactive astrogliosis in all animal groups. These findings indicate that estradiol, raloxifene, and tamoxifen are potential candidates for the control of astrogliosis in young and older individuals and after a prolonged depletion of ovarian hormones.
- 504Maglione, A.; Rolla, S.; De Mercanti, S. F.; Cutrupi, S.; Clerico, M. The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View. Cells 2019, 8 (10), 1280, DOI: 10.3390/cells8101280[Crossref], [CAS], Google Scholar511https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnsFOktrw%253D&md5=e8a0b2188da433ff60b032b46d705c8dThe adaptive immune system in multiple sclerosis: an estrogen-mediated point of viewMaglione, Alessandro; Rolla, Simona; De Mercanti, Stefania Federica; Cutrupi, Santina; Clerico, MarinellaCells (2019), 8 (10), 1280CODEN: CELLC6; ISSN:2073-4409. (MDPI AG)Multiple sclerosis (MS) is a chronic central nervous system inflammatory disease that leads to demyelination and neurodegeneration. The third trimester of pregnancy, which is characterized by high levels of estrogens, has been shown to be assocd. with reduced relapse rates compared with the rates before pregnancy. These effects could be related to the anti-inflammatory properties of estrogens, which orchestrate the reshuffling of the immune system toward immunotolerance to allow for fetal growth. The action of these hormones is mediated by the transcriptional regulation activity of estrogen receptors (ERs). Estrogen levels and ER expression define a specific balance of immune cell types. In this review, we explore the role of estradiol (E2) and ERs in the adaptive immune system, with a focus on estrogen-mediated cellular, mol., and epigenetic mechanisms related to immune tolerance and neuroprotection in MS. The epigenome dynamics of immune systems are described as key mol. mechanisms that act on the regulation of immune cell identity. This is a completely unexplored field, suggesting a future path for more extensive research on estrogen-induced coregulatory complexes and mol. circuitry as targets for therapeutics in MS.
- 505Villa, A.; Vegeto, E.; Poletti, A.; Maggi, A. Estrogens, Neuroinflammation, and Neurodegeneration. Endocrine Reviews 2016, 37 (4), 372– 402, DOI: 10.1210/er.2016-1007[Crossref], [PubMed], [CAS], Google Scholar512https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXkt1ykur0%253D&md5=dd42df0f5162ee810532218379d8fba2Estrogens, neuroinflammation, and neurodegenerationVilla, Alessandro; Vegeto, Elisabetta; Poletti, Angelo; Maggi, AdrianaEndocrine Reviews (2016), 37 (4), 372-402CODEN: ERVIDP; ISSN:1945-7189. (Endocrine Society)Inflammatory activation of microglia is a hallmark of several disorders of the central nervous system. In addn. to protecting the brain against inflammatory insults, microglia are neuroprotective and play a significant role in maintaining neuronal connectivity, but the prolongation of an inflammatory status may limit the beneficial functions of these immune cells. The finding that estrogen receptors are present in monocyte-derived cells and that estrogens prevent and control the inflammatory response raise the question of the role that this sex steroid plays in the manifestation and progression of pathologies that have a clear sex difference in prevalence, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The present review aims to provide a crit. review of the current literature on the actions of estrogen in microglia and on the involvement of estrogen receptors in the manifestation of selected neurol. disorders. This current understanding highlights a research area that should be expanded to identify appropriate replacement therapies to slow the progression of such diseases.
- 506Lewis, D. K.; Johnson, A. B.; Stohlgren, S.; Harms, A.; Sohrabji, F. Effects of Estrogen Receptor Agonists on Regulation of the Inflammatory Response in Astrocytes from Young Adult and Middle-Aged Female Rats. J. Neuroimmunol. 2008, 195 (1–2), 47– 59, DOI: 10.1016/j.jneuroim.2008.01.006[Crossref], [PubMed], [CAS], Google Scholar513https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkvVOrsbg%253D&md5=872374adfa200953c44d7fdada8f3951Effects of estrogen receptor agonists on regulation of the inflammatory response in astrocytes from young adult and middle-aged female ratsLewis, Danielle K.; Johnson, Adam B.; Stohlgren, Shannon; Harms, Ashley; Sohrabji, FaridaJournal of Neuroimmunology (2008), 195 (1-2), 47-59CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)Estrogen has been shown to attenuate the inflammatory response following injury or lipopolysaccharide treatment in several organ systems. Estrogen's actions are transduced through two estrogen receptor sub-types, estrogen receptor (ER) -alpha and estrogen receptor-beta, whose actions may be overlapping or independent of each other. The present study examd. the effects of ERα- and ERβ-specific ligands in regulating the inflammatory response in primary astrocyte cultures. Pre-treatment with 17β-estradiol (ERα/ERβ agonist), HPTE (ERα agonist/ERβ antagonist) and DPN (ERβ agonist) led to attenuation of IL-1β, TNFα, and MMP-9 in astrocyte media derived from young adult (3-4 mos.) and reproductive senescent female (9-11 mos., acyclic) astrocyte cultures, while pretreatment with PPT (ERα agonist) attenuated IL-1β (but not MMP-9) in both young and senescent-derived astrocyte cultures. Our previous work detd. that 17β-estradiol was unable to attenuate the LPS-induced increase in IL-1β in olfactory bulb primary microglial cultures derived from either young adult or reproductive senescent females. In young adult-derived microglial cultures, the LPS-induced increase in IL-1β was not attenuated by pre-treatment with 17β-estradiol, PPT or HPTE. Interestingly, the ERβ agonist, DPN significantly decreased IL-1β following LPS treatment in young adult-derived microglia. Thus while both microglia and astrocytes synthesize and release inflammatory mediators, the present data shows that compds. which bind ERβ are more effective in attenuating proinflammatory cytokines in both cell types and may therefore be a more effective agent for future therapeutic use.
- 507Vegeto, E.; Belcredito, S.; Etteri, S.; Ghisletti, S.; Brusadelli, A.; Meda, C.; Krust, A.; Dupont, S.; Ciana, P.; Chambon, P.; Maggi, A. Estrogen Receptor-α Mediates the Brain Antiinflammatory Activity of Estradiol. Proc. Natl. Acad. Sci. U. S. A. 2003, 100 (16), 9614– 9619, DOI: 10.1073/pnas.1531957100[Crossref], [PubMed], [CAS], Google Scholar514https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmtlyrsrk%253D&md5=6286a2e8b5ca38f34cdb10362e1c7644Estrogen receptor-α mediates the brain antiinflammatory activity of estradiolVegeto, Elisabetta; Belcredito, Silvia; Etteri, Sabrina; Ghisletti, Serena; Brusadelli, Alessia; Meda, Clara; Krust, Andree; Dupont, Sonia; Ciana, Paolo; Chambon, Pierre; Maggi, AdrianaProceedings of the National Academy of Sciences of the United States of America (2003), 100 (16), 9614-9619CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Beyond the key role in reproductive and cognitive functions, estrogens have been shown to protect against neurodegeneration assocd. with acute and chronic injuries of the adult brain. Current hypotheses reconcile this activity with a direct effect of 17β-estradiol (E2) on neurons. Brain macrophages are also involved in E2 action on the brain. Systemic administration of hormone prevents, in a time- and dose-dependent manner, the activation of microglia and the recruitment of peripheral monocytes induced by intraventricular injection of lipopolysaccharide. This effect occurs by limiting the expression of neuroinflammatory mediators, such as the matrix metalloproteinase 9 and lysosomal enzymes and complement C3 receptor, as well as by preventing morphol. changes occurring in microglia during the inflammatory response. By injecting lipopolysaccharide in estrogen receptor (ER)-null mouse brains, the authors demonstrate that hormone action is mediated by activation of ERα but not of ERβ. The specific role of ERα is further confirmed by comparing the effects of ERs on the matrix metalloproteinase 9 promoter activity in transient transfection assays. Finally, the authors report that genetic ablation of ERα is assocd. with a spontaneous reactive phenotype of microglia in specific brain regions of adult ERα-null mice. Altogether, these results reveal a previously undescribed function for E2 in brain and provide a mechanism for its beneficial activity on neuroinflammatory pathologies. They also underline the key role of ERα in brain macrophage reactivity and hint toward the usefulness of ERα-specific drugs in hormone replacement therapy of inflammatory diseases.
- 508Bebo, B. F.; Fyfe-Johnson, A.; Adlard, K.; Beam, A. G.; Vandenbark, A. A.; Offner, H. Low-Dose Estrogen Therapy Ameliorates Experimental Autoimmune Encephalomyelitis in Two Different Inbred Mouse Strains. J. Immunol. 2001, 166 (3), 2080– 2089, DOI: 10.4049/jimmunol.166.3.2080[Crossref], [PubMed], [CAS], Google Scholar515https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhtVSisbo%253D&md5=41d9a80d6e90b9194c05b113ee8cc91eLow-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strainsBebo, Bruce F., Jr.; Fyfe-Johnson, Amber; Adlard, Kirsten; Beam, Aaron G.; Vandenbark, Arthur A.; Offner, HalinaJournal of Immunology (2001), 166 (3), 2080-2089CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)It has been proposed that homeostatic levels of estrogen can enhance female susceptibility to autoimmunity, whereas the heightened levels of estrogen assocd. with pregnancy are protective. This hypothesis was tested using the mouse model of exptl. autoimmune encephalomyelitis (EAE). Diestrus (<100 pg/mL in serum) levels of 17β-estradiol were found to significantly reduce the clin. manifestations of active EAE in both male and female mice. Estriol was also effective but at doses below those previously established for pregnancy. The redn. in diseases severity was accompanied by a coincident redn. in the no. and size of inflammatory foci in the CNS of estrogen (17β-estradiol or estriol)-treated mice. Recipients of encephalitogenic T cells from low-dose estrogen-treated mice developed less severe paralysis than mice receiving T cells from placebo-treated mice. A modest shift in Th1/Th2 balance suggested that low dose estrogen therapy could bias the immune reaction toward a protective anti-inflammatory cytokine response. However, estrogen treatment at the onset of active EAE failed to reduce disease severity, a result that is consistent with the hypothesis that naive cells are more sensitive to sex hormones than differentiated effector cells. These data suggest that treatment with low doses of estrogen can reduce the capacity of developing myelin-reactive T cells to initiate disease and challenges the idea that increased susceptibility to autoimmunity in females is dependent on homeostatic levels of estrogen.
- 509Ito, A.; Bebo, B. F.; Matejuk, A.; Zamora, A.; Silverman, M.; Fyfe-Johnson, A.; Offner, H. Estrogen Treatment Down-Regulates TNF-α Production and Reduces the Severity of Experimental Autoimmune Encephalomyelitis in Cytokine Knockout Mice. J. Immunol. 2001, 167 (1), 542– 552, DOI: 10.4049/jimmunol.167.1.542[Crossref], [PubMed], [CAS], Google Scholar516https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXkslWjsL0%253D&md5=71c5a4fc4ad83f15089a61002bb01e78Estrogen treatment down-regulates TNF-α production and reduces the severity of experimental autoimmune encephalomyelitis in cytokine knockout miceIto, Atsushi; Bebo, Bruce F., Jr.; Matejuk, Agata; Zamora, Alex; Silverman, Marc; Fyfe-Johnson, Amber; Offner, HalinaJournal of Immunology (2001), 167 (1), 542-552CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)A shift toward Th2 cytokine prodn. has been demonstrated during pregnancy and high dose estrogen therapy and is thought to be the primary mechanism by which estrogen suppresses the development of exptl. autoimmune encephalomyelitis. However, low dose estrogen treatment is equally protective in the absence of a significant shift in cytokine prodn. In this study cytokine-deficient mice were treated with estrogen to det. whether a shift in Th2 cytokine prodn. was required for the protective effects of hormone therapy. Estrogen effectively suppressed the development of exptl. autoimmune encephalomyelitis in IL-4 and IL-10 knockout mice and in wild type littermate mice with a similar potency of protection. Significant disease suppression was also seen in IFN-γ-deficient mice. The decrease in disease severity was accompanied by a concomitant redn. in the no. of proinflammatory cytokine- and chemokine-producing cells in the CNS. Although there was no apparent increase in compensatory Th2 cytokine prodn. in cytokine-deficient mice, there was a profound decrease in the frequency of TNF-α-producing cells in the CNS and the periphery. Therefore, the authors propose that one mechanism by which estrogen protects females from the development of cell-mediated autoimmunity is through a hormone-dependent regulation of TNF-α prodn.
- 510Liu, H. Y.; Buenafe, A. C.; Matejuk, A.; Ito, A.; Zamora, A.; Dwyer, J.; Vandenbark, A. A.; Offner, H. Estrogen Inhibition of EAE Involves Effects on Dendritic Cell Function. J. Neurosci. Res. 2002, 70 (2), 238– 248, DOI: 10.1002/jnr.10409[Crossref], [PubMed], [CAS], Google Scholar517https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XnvFSlur4%253D&md5=34eae794c1b30db61d5287a3db89487cEstrogen inhibition of EAE involves effects on dendritic cell functionLiu, Hong Yan; Buenafe, Abigail C.; Matejuk, Agata; Ito, Atsushi; Zamora, Alex; Dwyer, Jami; Vandenbark, Arthur A.; Offner, HalinaJournal of Neuroscience Research (2002), 70 (2), 238-248CODEN: JNREDK; ISSN:0360-4012. (Wiley-Liss, Inc.)Estrogen has been found to have suppressive effects on the induction of exptl. autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. We have investigated the effects of 17β-estradiol (E2) treatment on dendritic cells (DCs) in two different mouse models of EAE. The frequency of CD11b+/CD11c+ DCs was significantly decreased in the brain of mice protected from EAE induction by E2 treatment. In addn., the frequency of CD11c+/CD8α+ DCs producing tumor necrosis factor (TNF)α and interferon (IFN)γ in the spleen of E2-treated mice was dramatically decreased compared to that in control mice with EAE, demonstrating an effect of E2 on DC function. In order to examine E2 effects on DCs in more detail, splenic DCs were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 to promote maturation. E2 pretreatment was found to suppress the ability of cultured DCs bearing a mature phenotype to present Ag to myelin basic protein (MBP)-specific T cells. Anal. of cytokine prodn. demonstrated that E2 decreased TNFα, IFNγ and IL-12 prodn. in mature DCs. In addn., MBP-specific T cells cocultured with E2-pretreated mature DCs in the presence of antigen demonstrated a shift towards prodn. of Th2 cytokines IL-4 and IL-10 and a concomitant decrease in the prodn. of Th1 cytokines TNFα and IFNγ. Thus, E2 treatment appears to have multiple effects on the DC population, which may contribute to a down-regulation or block in the activation of Th1 cells involved in the induction of EAE.
- 511Spence, R. D.; Hamby, M. E.; Umeda, E.; Itoh, N.; Du, S.; Wisdom, A. J.; Cao, Y.; Bondar, G.; Lam, J.; Ao, Y.; Sandoval, F.; Suriany, S.; Sofroniew, M. V.; Voskuhl, R. R. Neuroprotection Mediated through Estrogen Receptor-α in Astrocytes. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (21), 8867– 8872, DOI: 10.1073/pnas.1103833108[Crossref], [PubMed], [CAS], Google Scholar518https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntVegu7k%253D&md5=09da3b9932bf86a640ec1a0159148543Neuroprotection mediated through estrogen receptor-α in astrocytesSpence, Rory D.; Hamby, Mary E.; Umeda, Elizabeth; Itoh, Noriko; Du, Sienmi; Wisdom, Amy J.; Cao, Yuan; Bondar, Galyna; Lam, Jeannie; Ao, Yan; Sandoval, Francisco; Suriany, Silvie; Sofroniew, Michael V.; Voskuhl, Rhonda R.Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (21), 8867-8872, S8867/1-S8867/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Estrogen has well-documented neuroprotective effects in a variety of clin. and exptl. disorders of the CNS, including autoimmune inflammation, traumatic injury, stroke, and neurodegenerative diseases. The beneficial effects of estrogens in CNS disorders include mitigation of clin. symptoms, as well as attenuation of histopathol. signs of neurodegeneration and inflammation. The cellular mechanisms that underlie these CNS effects of estrogens are uncertain, because a no. of different cell types express estrogen receptors in the peripheral immune system and the CNS. Here, we investigated the potential roles of two endogenous CNS cell types in estrogen-mediated neuroprotection. We selectively deleted estrogen receptor-α (ERα) from either neurons or astrocytes using well-characterized Cre-loxP systems for conditional gene knockout in mice, and studied the effects of these conditional gene deletions on ERα ligand-mediated neuroprotective effects in a well-characterized model of adoptive exptl. autoimmune encephalomyelitis (EAE). We found that the pronounced and significant neuroprotective effects of systemic treatment with ERα ligand on clin. function, CNS inflammation, and axonal loss during EAE were completely prevented by conditional deletion of ERα from astrocytes, whereas conditional deletion of ERα from neurons had no significant effect. These findings show that signaling through ERα in astrocytes, but not through ERα in neurons, is essential for the beneficial effects of ERα ligand in EAE. Our findings reveal a unique cellular mechanism for estrogen-mediated CNS neuroprotective effects by signaling through astrocytes, and have implications for understanding the pathophysiol. of sex hormone effects in diverse CNS disorders.
- 512Kim, S.; Liva, S. M.; Dalal, M. A.; Verity, M. A.; Voskuhl, R. R. Estriol Ameliorates Autoimmune Demyelinating Disease: Implications for Multiple Sclerosis. Neurology 1999, 52 (6), 1230– 1238, DOI: 10.1212/WNL.52.6.1230[Crossref], [PubMed], [CAS], Google Scholar519https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXivVyqtL8%253D&md5=2b1a61a4d1f5a430ab48366141aba710Estriol ameliorates autoimmune demyelinating disease. Implications for multiple sclerosisKim, S.; Liva, S. M.; Dalal, M. A.; Verity, M. A.; Voskuhl, R. R.Neurology (1999), 52 (6), 1230-1238CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)To evaluate the use of estriol in the treatment of exptl. autoimmune encephalomyelitis (EAE) and other cell mediated autoimmune diseases. Exptl. autoimmune encephalomyelitis is a T helper 1 (Th1)-mediated autoimmune demyelinating disease that is a useful model for the study of immune responses in MS. Interestingly, both EAE and MS have been shown to be ameliorated during late pregnancy. Estriol, progesterone, and placebo pellets were implanted in mice during the effector phase of adoptive EAE. Disease scores were compared between treatment groups, and autoantigen-specific humoral and cellular responses were examd. Estriol treatment reduced the severity of EAE significantly compared with placebo treatment whereas progesterone treatment had no effect. Estriol doses that induced serum estriol levels that approximated estriol levels during late pregnancy were capable of ameliorating disease. Estriol-treated EAE mice had significantly higher levels of serum antibodies of the IgG1 isotype specific for the autoantigen myelin basic protein (MBP). Further, MBP-specific T-lymphocyte responses from estriol-treated EAE mice were characterized by significantly increased prodn. of the Th2 cytokine interleukin 10 (IL-10). T lymphocytes were shown to be the primary source of IL-10 within antigen-stimulated splenocyte populations. Estriol as a hormone involved in immune changes during pregnancy may provide a basis for the novel therapeutic use of estriol for MS and other putative Th1-mediated autoimmune diseases that improve during late pregnancy.
- 513Spence, R. D.; Wisdom, A. J.; Cao, Y.; Hill, H. M.; Mongerson, C. R. L.; Stapornkul, B.; Itoh, N.; Sofroniew, M. V.; Voskuhl, R. R. Estrogen Mediates Neuroprotection and Anti-Inflammatory Effects during EAE through ERα Signaling on Astrocytes but Not through ERβ Signaling on Astrocytes or Neurons. J. Neurosci. 2013, 33 (26), 10924– 10933, DOI: 10.1523/JNEUROSCI.0886-13.2013[Crossref], [PubMed], [CAS], Google Scholar520https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVKgu7nN&md5=95a24541ca9fd1877dbdb236e6d74b5fEstrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERα signaling on astrocytes but not through ERβ signaling on astrocytes or neuronsSpence, Rory D.; Wisdom, Amy J.; Cao, Yuan; Hill, Haley M.; Mongerson, Chandler R. L.; Stapornkul, Briana; Itoh, Noriko; Sofroniew, Michael V.; Voskuhl, Rhonda R.Journal of Neuroscience (2013), 33 (26), 10924-10933CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Estrogens can signal through either estrogen receptor α (ERα) or β (ERβ) to ameliorate exptl. autoimmune encephalomyelitis (EAE), the most widely used mouse model of multiple sclerosis (MS). Cellular targets of estrogen-mediated neuroprotection are still being elucidated. Previously, we demonstrated that ERα on astrocytes, but not neurons, was crit. for ERα ligand-mediated neuroprotection in EAE, including decreased T-cell and macrophage inflammation and decreased axonal loss. Here, we detd. whether ERβ on astrocytes or neurons could mediate neuroprotection in EAE, by selectively removing ERβ from either of these cell types using Cre-loxP gene deletion. Our results demonstrated that, even though ERβ ligand treatment was neuroprotective in EAE, this neuroprotection was not mediated through ERβ on either astrocytes or neurons and did not involve a redn. in levels of CNS inflammation. Given the differential neuroprotective and anti-inflammatory effects mediated via ERα vs. ERβ on astrocytes, we looked for mols. within astrocytes that were affected by signaling through ERα, but not ERβ. We found that ERα ligand treatment, but not ERβ ligand treatment, decreased expression of the chemokines CCL2 and CCL7 by astrocytes in EAE. Together, our data show that neuroprotection in EAE mediated via ERβ signaling does not require ERβ on either astrocytes or neurons, whereas neuroprotection in EAE mediated via ERα signaling requires ERα on astrocytes and reduces astrocyte expression of proinflammatory chemokines. These findings reveal important cellular differences in the neuroprotective mechanisms of estrogen signaling through ERα and ERβ in EAE.
- 514Sicotte, N. L.; Liva, S. M.; Klutch, R.; Pfeiffer, P.; Bouvier, S.; Odesa, S.; Wu, T. C. J.; Voskuhl, R. R. Treatment of Multiple Sclerosis with the Pregnancy Hormone Estriol. Ann. Neurol. 2002, 52 (4), 421– 428, DOI: 10.1002/ana.10301[Crossref], [PubMed], [CAS], Google Scholar521https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotlOjsbk%253D&md5=d862a1e452201bfbf1cc8acc831db03bTreatment of multiple sclerosis with the pregnancy hormone estriolSicotte, Nancy L.; Liva, Stephanie M.; Klutch, Rochelle; Pfeiffer, Paul; Bouvier, Seth; Odesa, Sylvia; Wu, T. C. Jackson; Voskuhl, Rhonda R.Annals of Neurology (2002), 52 (4), 421-428CODEN: ANNED3; ISSN:0364-5134. (Wiley-Liss, Inc.)Multiple sclerosis patients who become pregnant experience a significant decrease in relapses that may be mediated by a shift in immune responses from T helper 1 to T helper 2. Animal models of multiple sclerosis have shown that the pregnancy hormone, estriol, can ameliorate disease and can cause an immune shift. We treated nonpregnant female multiple sclerosis patients with the pregnancy hormone estriol in an attempt to recapitulate the beneficial effect of pregnancy. As compared with pretreatment baseline, relapsing remitting patients treated with oral estriol (8mg/day) demonstrated significant decreases in delayed type hypersensitivity responses to tetanus, interferon-γ levels in peripheral blood mononuclear cells, and gadolinium enhancing lesion nos. and vols. on monthly cerebral magnetic resonance images. When estriol treatment was stopped, enhancing lesions increased to pretreatment levels. When estriol treatment was reinstituted, enhancing lesions again were significantly decreased. Based on these results, a larger, placebo-controlled trial of estriol is warranted in women with relapsing remitting multiple sclerosis. This novel treatment strategy of using pregnancy doses of estriol in multiple sclerosis has relevance to other autoimmune diseases that also improve during pregnancy.
- 515Vukusic, S.; Ionescu, I.; El-Etr, M.; Schumacher, M.; Baulieu, E. E.; Cornu, C.; Confavreux, C. The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART′MUS) Trial: Rationale, Objectives and State of Advancement. J. Neurol. Sci. 2009, 286 (1–2), 114– 118, DOI: 10.1016/j.jns.2009.08.056[Crossref], [PubMed], [CAS], Google Scholar522https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1Cmur7P&md5=9c07fb1a6d469e5189a3ce0f437a8b98The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART'MUS) trial: Rationale, objectives and state of advancementVukusic, S.; Ionescu, I.; El-Etr, M.; Schumacher, M.; Baulieu, E. E.; Cornu, C.; Confavreux, C.Journal of the Neurological Sciences (2009), 286 (1-2), 114-118CODEN: JNSCAG; ISSN:0022-510X. (Elsevier B.V.)Multiple sclerosis (MS) affects 1 in 1000 people in western countries, mainly women in their childbearing years. It is an autoimmune disease of the central nervous system, which results in a chronic focal inflammatory response with subsequent demyelination and axonal loss. It usually begins with acute episodes of neurol. dysfunction, the relapses, followed by periods of partial or complete remission. This relapsing-remitting phase is usually followed by a steady, continuous and irreversible worsening of the neurol. dysfunction, which characterizes the progressive phase of the disease. Recent prospective studies reported a significant decline by two-third in the rate of relapses during the third trimester of pregnancy and a significant increase by two-third during the first three months post-partum by comparison to the relapse rate obsd. during the year prior to the pregnancy. These dramatic changes in the relapse rate occur at a time when impregnation of many substances, among which sexual steroids, is at its highest, before a dramatic decline to the pre-pregnancy levels, immediately following delivery. It may be hypothesized that sexual steroids could exert beneficial effects through a modulation of the immune state with a lowering of the pro-inflammatory lymphocyte responses of the Th1 type and an enhancement of anti-inflammatory responses of the Th2 type. They may also play a direct role in remyelination of central nervous system lesions, as they do in the peripheral nervous system, where progesterone increases the extent of myelin sheath formation after a cryolesion of the male mouse sciatic nerve. The POPART'MUS study is a European, multicenter, randomized, placebo-controlled and double-blind clin. trial, which aims to prevent MS relapses related to the post-partum condition, by administrating high doses of progestin, in combination with endometrial protective doses of estradiol. Treatment is given immediately after delivery and continuously during the first three months post-partum. At present, 126 patients have been enrolled and 107 patients have completed the protocol. Assuming the results of the trial to be pos., this new treatment could be considered in the relapsing-remitting phase of the disease in women afar from pregnancy and post-partum. The trial is registered under the ref. NTC00127075.
- 516Pozzilli, C.; De Giglio, L.; Barletta, V. T.; Marinelli, F.; De Angelis, F.; Gallo, V.; Pagano, V. A.; Marini, S.; Piattella, M. C.; Tomassini, V.; Pantano, P. Oral Contraceptives Combined with Interferon b in Multiple Sclerosis. Neurol. Neuroimmunol. NeuroInflammation 2015, 2 (4), e120, DOI: 10.1212/NXI.0000000000000120
- 517Voskuhl, R. R.; Wang, H. J.; Wu, T. C. J.; Sicotte, N. L.; Nakamura, K.; Kurth, F.; Itoh, N.; Bardens, J.; Bernard, J. T.; Corboy, J. R.; Cross, A. H.; Dhib-Jalbut, S.; Ford, C. C.; Frohman, E. M.; Giesser, B.; Jacobs, D.; Kasper, L. H.; Lynch, S.; Parry, G.; Racke, M. K.; Reder, A. T.; Rose, J.; Wingerchuk, D. M.; MacKenzie-Graham, A. J.; Arnold, D. L.; Tseng, C. H.; Elashoff, R. Estriol Combined with Glatiramer Acetate for Women with Relapsing-Remitting Multiple Sclerosis: A Randomised, Placebo-Controlled, Phase 2 Trial. Lancet Neurol. 2016, 15 (1), 35– 46, DOI: 10.1016/S1474-4422(15)00322-1[Crossref], [PubMed], [CAS], Google Scholar524https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFWlur3N&md5=c341048f0214951063df51f48472d3f0Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trialVoskuhl, Rhonda R.; Wang, HeJing; Wu, T. C. Jackson; Sicotte, Nancy L.; Nakamura, Kunio; Kurth, Florian; Itoh, Noriko; Bardens, Jenny; Bernard, Jacqueline T.; Corboy, John R.; Cross, Anne H.; Dhib-Jalbut, Suhayl; Ford, Corey C.; Frohman, Elliot M.; Giesser, Barbara; Jacobs, Dina; Kasper, Lloyd H.; Lynch, Sharon; Parry, Gareth; Racke, Michael K.; Reder, Anthony T.; Rose, John; Wingerchuk, Dean M.; MacKenzie-Graham, Allan J.; Arnold, Douglas L.; Tseng, Chi Hong; Elashoff, RobertLancet Neurology (2016), 15 (1), 35-46CODEN: LNAEAM; ISSN:1474-4422. (Elsevier Ltd.)Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclin. studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favorably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women. We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurol. centers in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 mo, with a significance level of p=0·10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Anal. was by intention to treat. The trial is registered with ClinicalTrials.gov, no. NCT00451204. We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0·25 relapses per yr (95% CI 0·17-0·37) in the estriol group vs. 0·37 relapses per yr (0·25-0·53) in the placebo group (adjusted rate ratio 0·63, 95% CI 0·37-1·05; p=0·077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0·0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0·0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clin. examn., mammogram, uterine ultrasound, or endometrial lining biopsy. Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 mo. These results warrant further investigation in a phase 3 trial. National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.
- 518Rossouw, J. E.; Anderson, G. L.; Prentice, R. L.; LaCroix, A. Z.; Kooperberg, C.; Stefanick, M. L.; Jackson, R. D.; Beresford, S. A. A.; Howard, B. V.; Johnson, K. C.; Kotchen, J. M.; Ockene, J. Risks and Benefits of Estrogen plus Progestin in Healthy Postmenopausal Women: Principal Results from the Women’s Health Initiative Randomized Controlled Trial. JAMA, J. Am. Med. Assoc. 2002, 288 (3), 321– 333, DOI: 10.1001/jama.288.3.321[Crossref], [PubMed], [CAS], Google Scholar525https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xltlegs7k%253D&md5=e1b284f6b24aca24dd44549ad91874d2Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the women's health initiative randomized controlled trialRossouw, Jacques E.; Anderson, Garnet L.; Prentice, Ross L.; LaCroix, Andrea Z.; Kooperberg, Charles; Stefanick, Marcia L.; Jackson, Rebecca D.; Beresford, Shirley A. A.; Howard, Barbara V.; Johnson, Karen C.; Morley-Kotchen, Jane; Ockene, JudithJAMA, the Journal of the American Medical Association (2002), 288 (3), 321-333CODEN: JAMAAP; ISSN:0098-7484. (American Medical Association)Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. Studies were carried out to assess the major health benefits and risks of the most commonly used combined hormone prepn. in the United States. The study design consisted of estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 yr) in which 16 608 postmenopausal women aged 50-79 yr with an intact uterus at baseline were recruited by 40 US clin. centers in 1993-1998. Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet or placebo. The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. On May 31, 2002, after a mean of 5.2 yr of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs. placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clin. outcomes through Apr. 30, 2002. Estd. hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Abs. excess risks per 10,000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while abs. risk redns. per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The abs. excess risk of events included in the global index was 19 per 10,000 person-years. Thus, overall health risks exceeded benefits from use of combined estrogen plus progestin for an av. 2-yr follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.
- 519Paterni, I.; Granchi, C.; Katzenellenbogen, J. A.; Minutolo, F. Estrogen Receptors Alpha (ERα) and Beta (ERβ): Subtype-Selective Ligands and Clinical Potential. Steroids 2014, 90, 13– 29, DOI: 10.1016/j.steroids.2014.06.012[Crossref], [PubMed], [CAS], Google Scholar526https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFenu7vI&md5=ac6863afe52e6a18ffd89d3ba6770023Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potentialPaterni, Ilaria; Granchi, Carlotta; Katzenellenbogen, John A.; Minutolo, FilippoSteroids (2014), 90 (), 13-29CODEN: STEDAM; ISSN:0039-128X. (Elsevier)A review. Estrogen receptors alpha (ERα) and beta (ERβ) are nuclear transcription factors that are involved in the regulation of many complex physiol. processes in humans. Modulation of these receptors by prospective therapeutic agents is currently being considered for prevention and treatment of a wide variety of pathol. conditions, such as, cancer, metabolic and cardiovascular diseases, neurodegeneration, inflammation, and osteoporosis. This review provides an overview and update of compds. that have been recently reported as modulators of ERs, with a particular focus on their potential clin. applications.
- 520Brzozowski, A. M.; Pike, A. C. W.; Dauter, Z.; Hubbard, R. E.; Bonn, T.; Engström, O.; Öhman, L.; Greene, G. L.; Gustafsson, J.-Å.; Carlquist, M. Molecular Basis of Agonism and Antagonism in the Oestrogen Receptor. Nature 1997, 389 (6652), 753– 758, DOI: 10.1038/39645[Crossref], [PubMed], [CAS], Google Scholar527https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmvVSnt74%253D&md5=2a63951b881b329ff142c9fbc82a13e3Molecular basis of agonism and antagonism in the estrogen receptorBrzozowski, Andrzej M.; Pike, Ashley C. W.; Dauter, Zbigniew; Hubbard, Roderick E.; Bonn, Tomas; Engstrom, Owe; Ohman, Lars; Greene, Geoffrey L.; Gustafsson, Jan-Ake; Carlquist, MatsNature (London) (1997), 389 (6652), 753-758CODEN: NATUAS; ISSN:0028-0836. (Macmillan Magazines)Estrogens are involved in the growth, development and homeostasis of a no. of tissues. The physiol. effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the estrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of mol. events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. Here we report the crystal structures of the LBD of ER in complex with the endogenous estrogen, 17β-estradiol, and the selective antagonist raloxifene, at resolns. of 3.1 and 2.6Å, resp. The structures provide a mol. basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes. In addn., each class of ligand induces a distinct conformation in the transactivation domain of the LBD, providing structural evidence of the mechanism of antagonism.
- 521Pike, A. C. W.; Brzozowski, A. M.; Hubbard, R. E.; Bonn, T.; Thorsell, A.-G.; Engström, O.; Ljunggren, J.; Gustafsson, J.-Å.; Carlquist, M. Structure of the Ligand-Binding Domain of Oestrogen Receptor Beta in the Presence of a Partial Agonist and a Full Antagonist. EMBO J. 1999, 18 (17), 4608– 4618, DOI: 10.1093/emboj/18.17.4608[Crossref], [PubMed], [CAS], Google Scholar528https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmt1yisLo%253D&md5=804a1a7c57ae5aed793f601241500febStructure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonistPike, Ashley C. W.; Brzozowski, Andrzej M.; Hubbard, Roderick E.; Bonn, Tomas; Thorsell, Ann-Gerd; Engstrom, Owe; Ljunggren, Jan; Gustafsson, Jan-Ake; Carlquist, MatsEMBO Journal (1999), 18 (17), 4608-4618CODEN: EMJODG; ISSN:0261-4189. (Oxford University Press)Estrogens exert their physiol. effects through two receptor subtypes. Here we report the three-dimensional structure of the estrogen receptor beta isoform (ERβ) ligand-binding domain (LBD) in the presence of the phyto-estrogen genistein and the antagonist raloxifene. The overall structure of ERβ-LBD is very similar to that previously reported for ERα. Each ligand interacts with a unique set of residues within the hormone-binding cavity and induces a distinct orientation in the AF-2 helix (H12). The bulky side chain of raloxifene protrudes from the cavity and phys. prevents the alignment of H12 over the bound ligand. In contrast, genistein is completely buried within the hydrophobic core of the protein and binds in a manner similar to that obsd. for ER's endogenous hormone, 17β-estradiol. However, in the ERβ-genistein complex, H12 does not adopt the distinctive "agonist" position but, instead, lies in a similar orientation to that induced by ER antagonists. Such a sub-optimal alignment of the transactivation helix is consistent with genistein's partial agonist character in ERβ and demonstrates how ER's transcriptional response to certain bound ligands is attenuated.
- 522Shiau, A. K.; Barstad, D.; Radek, J. T.; Meyers, M. J.; Nettles, K. W.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A.; Agard, D. A.; Greene, G. L. Structural Characterization of a Subtype-Selective Ligand Reveals a Novel Mode of Estrogen Receptor Antagonism. Nat. Struct. Biol. 2002, 9 (5), 359– 364, DOI: 10.1038/nsb787[Crossref], [PubMed], [CAS], Google Scholar529https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtFyrsrk%253D&md5=fb4b665e84466c50065a7b242104c364Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonismShiau, A. K.; Barstad, D.; Radek, J. T.; Meyers, M. J.; Nettles, K. W.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A.; Agard, D. A.; Greene, G. L.Nature Structural Biology (2002), 9 (5), 359-364CODEN: NSBIEW; ISSN:1072-8368. (Nature America Inc.)The R,R enantiomer of 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC) exerts opposite effects on the transcriptional activity of the two estrogen receptor (ER) subtypes, ERα and ERβ. THC acts as an ERα agonist and as an ERβ antagonist. We have detd. the crystal structures of the ERα ligand binding domain (LBD) bound to both THC and a fragment of the transcriptional coactivator GRIP1, and the ERβ LBD bound to THC. THC stabilizes a conformation of the ERα LBD that permits coactivator assocn. and a conformation of the ERβ LBD that prevents coactivator assocn. A comparison of the two structures, taken together with functional data, reveals that THC does not act on ERβ through the same mechanisms used by other known ER antagonists. Instead, THC antagonizes ERβ through a novel mechanism we term 'passive antagonism'.
- 523Levenson, A. S.; Craig Jordan, V. The Key to the Antiestrogenic Mechanism of Raloxifene Is Amino Acid 351 (Aspartate) in the Estrogen Receptor. Cancer Res. 1998, 58 (9), 1872– 1875[PubMed], [CAS], Google Scholar530https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXislentrs%253D&md5=3fd0451c44fa1112069453b6a8e8c496The key to the antiestrogenic mechanism of raloxifene is amino acid 351 (aspartate) in the estrogen receptorLevenson, Anait S.; Jordan, V. CraigCancer Research (1998), 58 (9), 1872-1875CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The crystn. of the ligand-binding domain (LBD) of the estrogen receptor (ER) with 17β-estradiol and raloxifene [A. M. Brzozowski et al., Nature (Lond.), 389: 753-758, 1997] now provides a mol. basis for the biol. activity of complexes as either agonists or antagonists. It is well established that the crit. structural feature of antiestrogens is a correctly positioned alkylaminoethoxy side chain. The X-ray crystallog. clearly shows that the alkylaminoethoxy side chain of raloxifene causes a specific and inappropriate mol. perturbation of the LBD and that the nitrogen in the side chain must hydrogen bond with aspartate 351 in the LBD of ER. We previously identified and characterized a naturally occurring mutation in the ER from a tamoxifen-stimulated transplantable human breast tumor line. The mutation is at AA351 of LBD, where the aspartate is changed to tyrosine (Asp351Tyr). In this report, we compared and contrasted the pharmacol. of raloxifene to block or induce E2-stimulated increase in TGF-α mRNA in stable transfectants of ER-neg. human breast cancer cells with the cDNAs from wild-type, mutant-amino acid (AA) 400 ER and mutant-AA 351 ER. Our results show that the mutation at AA 351 that replaces aspartate by tyrosine specifically changes the pharmacol. of raloxifene from an antiestrogen to an estrogen. By contrast, a mutation at AA 400 does not, and the antiestrogenic properties of raloxifene are retained. These data and the fact that the nitrogen in the side chain must specifically interact with aspartate 351 makes this the key to the antiestrogenic activity of raloxifene.
- 524Heldring, N.; Pike, A.; Andersson, S.; Matthews, J.; Cheng, G.; Hartman, J.; Tujague, M.; Ström, A.; Treuter, E.; Warner, M.; Gustafsson, J.-Å. Estrogen Receptors: How Do They Signal and What Are Their Targets. Physiol. Rev. 2007, 87 (3), 905– 931, DOI: 10.1152/physrev.00026.2006[Crossref], [PubMed], [CAS], Google Scholar531https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXptFGls7k%253D&md5=207d16fa37d6b14483b9fe1002ce2646Estrogen receptors: how do they signal and what are their targetsHeldring, Nina; Pike, Ashley; Andersson, Sandra; Matthews, Jason; Cheng, Guojun; Hartman, Johan; Tujague, Michel; Stroem, Anders; Treuter, Eckardt; Warner, Margaret; Gustafsson, Jan-AakePhysiological Reviews (2007), 87 (3), 905-931CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)A review. During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clin. as well as a preclin. perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ERα and ERβ) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clin. areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Mol. biol., biochem., and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a no. of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the mol. mechanisms of anti-estrogen signaling.
- 525Nilsson, S.; Koehler, K. F.; Gustafsson, J.-Å. Development of Subtype-Selective Oestrogen Receptor-Based Therapeutics. Nat. Rev. Drug Discovery 2011, 10 (10), 778– 792, DOI: 10.1038/nrd3551[Crossref], [PubMed], [CAS], Google Scholar532https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFOlsL7K&md5=dbd864f2c3be58434d21049568c1e348Development of subtype-selective oestrogen receptor-based therapeuticsNilsson, Stefan; Koehler, Konrad F.; Gustafsson, Jan-AakeNature Reviews Drug Discovery (2011), 10 (10), 778-792CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. The two estrogen receptor subtypes α and β are hormone-regulated modulators of intracellular signalling and gene expression. Regulation of estrogen receptor activity is crucial not only for development and homeostasis but also for the treatment of various diseases and symptoms. Classical selective estrogen receptor modulators are well established in the treatment of breast cancer and osteoporosis, but emerging data suggest that the development of subtype-selective ligands that specifically target either estrogen receptor-α or estrogen receptor-β could be a more optimal approach for the treatment of cancer, cardiovascular disease, multiple sclerosis and Alzheimer's disease.
- 526Jordan, V. C. Antiestrogens and Selective Estrogen Receptor Modulators as Multifunctional Medicines. 1. Receptor Interactions. J. Med. Chem. 2003, 46, 883– 908, DOI: 10.1021/jm020449y[ACS Full Text], [CAS], Google Scholar533https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhtl2ku78%253D&md5=b86cc4c3c4a4698a51eac9ab69ae9122Antiestrogens and Selective Estrogen Receptor Modulators as Multifunctional Medicines. 1. Receptor InteractionsJordan, V. CraigJournal of Medicinal Chemistry (2003), 46 (6), 883-908CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Antiestrogens and selective Estrogen receptor modulators as multifunctional medicines are discussed.
- 527Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Pyrazole Ligands: Structure - Affinity/Activity Relationships and Estrogen Receptor-α-Selective Agonists. J. Med. Chem. 2000, 43 (26), 4934– 4947, DOI: 10.1021/jm000170m[ACS Full Text], [CAS], Google Scholar534https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXot1yjsbk%253D&md5=3bce249ad2d0eaf91aa4ad17ebffdd05Pyrazole Ligands: Structure-Affinity/Activity Relationships and Estrogen Receptor-α-Selective AgonistsStauffer, Shaun R.; Coletta, Christopher J.; Tedesco, Rosanna; Nishiguchi, Gisele; Carlson, Kathryn; Sun, Jun; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.Journal of Medicinal Chemistry (2000), 43 (26), 4934-4947CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) and that one pyrazole is considerably more potent as an agonist on the ERα than on the ERβ subtype. To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ERα-selective agonist, we prepd. a no. of tetrasubstituted pyrazole analogs with defined variations at certain substituent positions. Anal. of their binding affinity pattern shows that a C(4)-Pr substituent is optimal and that a p-hydroxyl group on the N(1)-Ph group also enhances affinity and selectivity for ERα. The best compd. in this series, a propylpyrazole triol (I), binds to ERα with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ERα. It also activates gene transcription only through ERα. Thus, this compd. represents the first ERα-specific agonist. We investigated the mol. basis for the exceptional ERα binding affinity and potency selectivity of pyrazole I by a further study of structure-affinity relationships in this series and by mol. modeling. These investigations suggest that the pyrazole triols prefer to bind to ERα with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-Pr group with portions of the receptor where ERα has a smaller residue than ERβ. These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biol. activities in estrogen target cells that can be selectively activated through ERα.
- 528Meyers, M. J.; Sun, J.; Carlson, K. E.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Estrogen Receptor Subtype-Selective Ligands: Asymmetric Synthesis and Biological Evaluation of Cis- and Trans-5,11-Dialkyl-5,6,11,12- Tetrahydrochrysenes. J. Med. Chem. 1999, 42 (13), 2456– 2468, DOI: 10.1021/jm990101b[ACS Full Text], [CAS], Google Scholar535https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXjtlClt7Y%253D&md5=9e41afa29dec2419ab105ebb09615fb5Estrogen Receptor Subtype-Selective Ligands: Asymmetric Synthesis and Biological Evaluation of cis- and trans-5,11-Dialkyl- 5,6,11,12-tetrahydrochrysenesMeyers, Marvin J.; Sun, Jun; Carlson, Kathryn E.; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.Journal of Medicinal Chemistry (1999), 42 (13), 2456-2468CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)It was recently reported that racemic 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC) acts as an agonist on estrogen receptor alpha (ERα) and as a complete antagonist on estrogen receptor beta (ERβ). To further investigate this novel ER subtype-selective estrogenic activity, a series of cis- and trans-dialkyl THCs was synthesized. Cis-di-Me, cis-di-Et, and cis-di-Pr THCs were prepd. in a highly enantio- and diastereoselective manner by the acyloin condensation of enantiomerically pure α-alkyl-β-arylpropionic esters, followed by a Lewis acid-mediated double cyclization under conditions of minimal epimerization. ERα and ERβ binding affinity of both cis and trans isomers of di-Me, di-Et, and di-Pr THCs was detd. in competitive binding assays, and their transcriptional activity was detd. in reporter gene assays in mammalian cells. Nearly all THCs examd. were found to be affinity-selective for ERβ. All these THCs are agonists on ERα, and THCs with small substituents are agonists on both ERα and ERβ. As substituent size was increased, ERβ-selective antagonism developed first in the (R,R)-cis enantiomer series and finally in the trans diastereomer and (S,S)-cis enantiomer series. The most potent and selective ligand was identified as (R,R)-cis-diethyl THC 2b, which mimicked the ERβ-selective antagonist character of racemic cis-di-Et THC. This study illustrates that the antagonist character in THC ligands for ERβ depends in a progressive way on the size and geometric disposition of substituent groups and suggests that the induction of an antagonist conformation in ERβ can be achieved with these ligands with less steric perturbation than in ERα. Furthermore, antagonists that are selectively effective on ERβ can have structures that are very different from the typical antiestrogens tamoxifen and raloxifene, which are antagonists on both ERα and ERβ.
- 529Meyers, M. J.; Sun, J.; Carlson, K. E.; Marriner, G. A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Estrogen Receptor-β Potency-Selective Ligands: Structure-Activity Relationship Studies of Diarylpropionitriles and Their Acetylene and Polar Analogues. J. Med. Chem. 2001, 44 (24), 4230– 4251, DOI: 10.1021/jm010254a[ACS Full Text], [CAS], Google Scholar536https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnsFagsr8%253D&md5=8fbf46c36aaf2ffcc9a8c44b15827bfeEstrogen Receptor-β Potency-Selective Ligands: Structure-Activity Relationship Studies of Diarylpropionitriles and Their Acetylene and Polar AnaloguesMeyers, Marvin J.; Sun, Jun; Carlson, Kathryn E.; Marriner, Gwendolyn A.; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.Journal of Medicinal Chemistry (2001), 44 (24), 4230-4251CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Through an effort to develop novel ligands that have subtype selectivity for the estrogen receptors alpha (ERα) and beta (ERβ), we have found that 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) acts as an agonist on both ER subtypes, but has a 70-fold higher relative binding affinity and 170-fold higher relative potency in transcription assays with ERβ than with ERα. To investigate the ERβ affinity- and potency-selective character of this DPN further, we prepd. a series of DPN analogs in which both the ligand core and the arom. rings were modified by the repositioning of phenolic hydroxy groups and by the addn. of alkyl substituents and nitrile groups. We also prepd. other series of DPN analogs in which the nitrile functionality was replaced with acetylene groups or polar functions, to mimic the linear geometry or polarity of the nitrile, resp. To varying degrees, all of the analogs show preferential binding affinity for ERβ (i.e., they are ERβ affinity-selective), and many, but not all of them, are also more potent in activating transcription through ERβ than through ERα (i.e., they are ERβ potency-selective). meso-2,3-Bis(4-hydroxyphenyl)succinonitrile and dl-2,3-bis(4-hydroxyphenyl)succinonitrile are among the highest ERβ affinity-selective ligands, and they have an ERβ potency selectivity that is equiv. to that of DPN. The acetylene analogs have higher binding affinities but somewhat lower selectivities than their nitrile counterparts. The polar analogs have lower affinities, and only the fluorinated polar analogs have substantial affinity selectivities. This study suggests that, in this series of ligands, the nitrile functionality is crit. to ERβ selectivity because it provides the optimal combination of linear geometry and polarity. Furthermore, the addn. of a second nitrile group β to the nitrile in DPN or the addn. of a Me substituent at an ortho position on the β-arom. ring increases the affinity and selectivity of these compds. for ERβ. These ERβ-selective compds. may prove to be valuable tools in understanding the differences in structure and biol. function of ERα and ERβ.
- 530Minutolo, F.; Bertini, S.; Granchi, C.; Marchitiello, T.; Prota, G.; Rapposelli, S.; Tuccinardi, T.; Martinelli, A.; Gunther, J. R.; Carlson, K. E.; Katzenellenbogen, J. A.; Macchia, M. Structural Evolutions of Salicylaldoximes as Selective Agonists for Estrogen Receptor β. J. Med. Chem. 2009, 52 (3), 858– 867, DOI: 10.1021/jm801458t[ACS Full Text], [CAS], Google Scholar537https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktVygtw%253D%253D&md5=f3846088c752542e30c8590647a6c0daStructural Evolutions of Salicylaldoximes as Selective Agonists for Estrogen Receptor βMinutolo, Filippo; Bertini, Simone; Granchi, Carlotta; Marchitiello, Teresa; Prota, Giovanni; Rapposelli, Simona; Tuccinardi, Tiziano; Martinelli, Adriano; Gunther, Jillian R.; Carlson, Kathryn E.; Katzenellenbogen, John A.; Macchia, MarcoJournal of Medicinal Chemistry (2009), 52 (3), 858-867CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The bioisosteric replacement of the phenol ring, a signature functional group of most estrogen receptor (ER) ligands, with a hydrogen-bonded pseudocyclic ring, led to the development of a novel class of non-steroidal ER-ligands based on a salicylaldoxime template. A series of structural modifications were applied to selected mols. belonging to the monoaryl-salicylaldoxime chem. class in an attempt to improve further their ERβ-selective receptor affinity and agonist properties. Among several modifications, the best results were obtained by the simultaneous introduction of a meta-fluorine atom into the para-hydroxyphenyl substituent present in the 4-position of salicylaldoxime, together with the insertion of a chloro group in the 3-position of the central scaffold. The resulting compd. showed the best affinity (Ki = 7.1 nM) and selectivity for ERβ over ERα. Moreover, in transcription assays, it proved to be a selective and potent ERβ-full agonist with an EC50 of 4.8 nM.
- 531Malamas, M. S.; Manas, E. S.; McDevitt, R. E.; Gunawan, I.; Xu, Z. B.; Collini, M. D.; Miller, C. P.; Dinh, T.; Henderson, R. A.; Keith, J. C.; Harris, H. A. Design and Synthesis of Aryl Diphenolic Azoles as Potent and Selective Estrogen Receptor-β Ligands. J. Med. Chem. 2004, 47 (21), 5021– 5040, DOI: 10.1021/jm049719y[ACS Full Text], [CAS], Google Scholar538https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXnt12gtrc%253D&md5=01c7d1d0fb71105c1adffeb5f0bc7d3bDesign and Synthesis of Aryl Diphenolic Azoles as Potent and Selective Estrogen Receptor-β LigandsMalamas, Michael S.; Manas, Eric S.; McDevitt, Robert E.; Gunawan, Iwan; Xu, Zhang B.; Collini, Michael D.; Miller, Chris P.; Dinh, Tam; Henderson, Ruth A.; Keith, James C., Jr.; Harris, Heather A.Journal of Medicinal Chemistry (2004), 47 (21), 5021-5040CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)New diphenolic azoles as highly selective estrogen receptor-β agonists are reported. The more potent and selective analogs of these series have comparable binding affinities for ERβ as the natural ligand 17β-estradiol but are >100-fold selective over ERα. The design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERβ cocrystd. with various ligands as well as mol. modeling studies. These strategies enabled the use of a single conservative residue substitution in the ligand-binding pocket, ERα Met421 → ERβ Ile373, to optimize ERβ selectivity. The 7-position-substituted benzoxazoles were the most selective ligands of both azole series, with ERB-041 (I) being >200-fold selective for ERβ. The majority of ERβ selective agonists tested that were at least ∼50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERβ-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
- 532Komm, B. S.; Mirkin, S. An Overview of Current and Emerging SERMs. J. Steroid Biochem. Mol. Biol. 2014, 143, 207– 222, DOI: 10.1016/j.jsbmb.2014.03.003[Crossref], [PubMed], [CAS], Google Scholar539https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVaksrjK&md5=18074eedb314d30864441d3f57cc4880An overview of current and emerging SERMsKomm, Barry S.; Mirkin, SebastianJournal of Steroid Biochemistry and Molecular Biology (2014), 143 (), 207-222CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)A review. Selective estrogen receptor modulators (SERMs) are compds. that exhibit tissue-specific estrogen receptor (ER) agonist or antagonist activity, and are used for various indications, including treatment of breast cancer, osteoporosis, and menopausal symptoms. Endometrial safety has been a key differentiator between SERMs in clin. practice. For example, tamoxifen exhibits ER agonist activity in the uterus, resulting in an increased risk of endometrial hyperplasia and malignancy, whereas raloxifene and bazedoxifene have neutral effects on the uterus. Based on their efficacy and long-term safety, SERMs are increasingly being prescribed for women who cannot tolerate other treatment options and for younger women at an increased risk of fracture who may remain on therapy for long periods of time. Continuing advances in the understanding of SERM mechanisms of action and structural interactions with the ER may lead to the development of new agents and combinations of agents to provide optimal treatments to meet the varying needs of postmenopausal women. One such example is the tissue selective estrogen complex, which partners a SERM with 1 or more estrogens, with the aim of blending the desired estrogen-receptor agonist activities of estrogens on vasomotor symptoms, vulvar-vaginal atrophy, and loss of bone mass with the tissue selectivity of a SERM.
- 533Patel, H. K.; Bihani, T. Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs) in Cancer Treatment. Pharmacol. Ther. 2018, 186, 1– 24, DOI: 10.1016/j.pharmthera.2017.12.012[Crossref], [PubMed], [CAS], Google Scholar540https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXovVShtw%253D%253D&md5=9e33ceed330cba071400fd70c0b71bf4Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatmentPatel, Hitisha K.; Bihani, TeeruPharmacology & Therapeutics (2018), 186 (), 1-24CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)Breast cancer is the most frequently diagnosed cancer in women, with estrogen receptor pos. (ER+) breast cancer making up approx. 75% of all breast cancers diagnosed. Given the dependence on active ER signaling in these tumors, the predominant treatment strategy has been to inhibit various aspects of this pathway including directly antagonizing ER with the use of selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). Interestingly, the dependence on ER for breast cancer growth is often retained even after progression through several lines of antiestrogen therapy, making ER a bonafide biomarker for this cancer subtype and driving the continued research and development of novel ER-targeted therapeutics to treat this patient population. This, combined with the continuous discovery of mechanisms underlying endocrine resistance, is resulting in a continually evolving treatment landscape for ER+ breast cancer. This review discusses various ER antagonists investigated for the treatment of breast cancer, outlining their pharmacol. and tissue-specific mechanisms of action as well as their specified use within the ER+ breast cancer setting. In addn., mechanisms of resistance to SERMs and SERDs, the use of ER antagonists in combination therapy strategies, and the ongoing development of novel drugs are also reviewed in the context of the changing clin. landscape of ER+ breast cancer. Lastly, the role of SERMs and SERDs in non-breast cancer indications is also discussed.
- 534Henke, B. R.; Drewry, D. H.; Jones, S. A.; Stewart, E. L.; Weaver, S. L.; Wiethe, R. W. 2-Amino-4,6-Diarylpyridines as Novel Ligands for the Estrogen Receptor. Bioorg. Med. Chem. Lett. 2001, 11 (14), 1939– 1942, DOI: 10.1016/S0960-894X(01)00321-3[Crossref], [PubMed], [CAS], Google Scholar541https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXltFylsb4%253D&md5=142e9f4a508e764440a048d657d6e0322-Amino-4,6-diarylpyridines as novel ligands for the estrogen receptorHenke, B. R.; Drewry, D. H.; Jones, S. A.; Stewart, E. L.; Weaver, S. L.; Wiethe, R. W.Bioorganic & Medicinal Chemistry Letters (2001), 11 (14), 1939-1942CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)A novel series of 2-amino-4,6-diarylpyridines were prepd. that function as ligands of estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). These compds. bind to both ERα and ERβ with a modest selectivity for the alpha subtype. The most potent of these analogs, compd. I, has a Ki=20 nM at ERα. These mols. represent a novel template for designing potentially useful ligands for the estrogen receptor.
- 535Renaud, J.; Bischoff, S. F.; Buhl, T.; Floersheim, P.; Fournier, B.; Geiser, M.; Halleux, C.; Kallen, J.; Keller, H.; Ramage, P. Selective Estrogen Receptor Modulators with Conformationally Restricted Side Chains. Synthesis and Structure-Activity Relationship of ERα-Selective Tetrahydroisoquinoline Ligands. J. Med. Chem. 2005, 48 (2), 364– 379, DOI: 10.1021/jm040858p[ACS Full Text], [CAS], Google Scholar542https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtFCiu7fN&md5=78fb4980fb466d857a1c767671dd0f31Selective Estrogen Receptor Modulators with Conformationally Restricted Side Chains. Synthesis and Structure-Activity Relationship of ERα-Selective Tetrahydroisoquinoline LigandsRenaud, Johanne; Bischoff, Serge Francois; Buhl, Thomas; Floersheim, Philipp; Fournier, Brigitte; Geiser, Martin; Halleux, Christine; Kallen, Joerg; Keller, Hansjoerg; Ramage, PaulJournal of Medicinal Chemistry (2005), 48 (2), 364-379CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors disclose herein the discovery of estrogen receptor α (ERα) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Mol. modeling studies used in conjunction with the x-ray crystal structure of the ERα ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compd. I was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline II. In addn. to exhibiting a binding affinity to ERα and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compd. I, ligand II showed a reduced agonist behavior in the MCF-7 assay in the absence of 17β-estradiol. These data point toward the fact that II may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic expt. carried out in rats, II displayed an interesting profile, with a bioavailability of 49%. The authors also disclose the x-ray crystal structure of II in complex with ERα-LBD, which reveals the preferred configurations of II at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogs bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted Ph D-ring increases the selectivity of a set of piperazinyl-contg. ligands in favor of ERα over ERβ.
- 536Hill, R. A.; Kouremenos, K.; Tull, D.; Maggi, A.; Schroeder, A.; Gibbons, A.; Kulkarni, J.; Sundram, S.; Du, X. Bazedoxifene – a Promising Brain Active SERM That Crosses the Blood Brain Barrier and Enhances Spatial Memory. Psychoneuroendocrinology 2020, 121, 104830, DOI: 10.1016/j.psyneuen.2020.104830[Crossref], [PubMed], [CAS], Google Scholar543https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1yjsLrJ&md5=d49dbaac0b1c60ca0b4b715df2182908Bazedoxifene - a promising brain active SERM that crosses the blood brain barrier and enhances spatial memoryHill, R. A.; Kouremenos, K.; Tull, D.; Maggi, A.; Schroeder, A.; Gibbons, A.; Kulkarni, J.; Sundram, S.; Du, X.Psychoneuroendocrinology (2020), 121 (), 104830CODEN: PSYCDE; ISSN:0306-4530. (Elsevier Ltd.)Over 20 years of accumulated evidence has shown that the major female sex hormone 17β-estradiol can enhance cognitive functioning. However, the utility of estradiol as a therapeutic cognitive enhancer is hindered by its unwanted peripheral effects (carcinogenic). Selective estrogen receptor modulators (SERMs) avoid the unwanted effects of estradiol by acting as estrogen receptor antagonists in some tissues such as breast and uterus, but as agonists in others such as bone, and are currently used for the treatment of osteoporosis. However, understanding of their actions in the brain are limited. The third generation SERM bazedoxifene has recently been FDA approved for clin. use with an improved biosafety profile. However, whether bazedoxifene can enter the brain and enhance cognition is unknown. Using mice, the current study aimed to explore if bazedoxifene can 1. cross the blood-brain barrier, 2. rescue ovariectomy-induced hippocampal-dependent spatial memory deficit, and 3. activity neural estrogen response element (ERE)-dependent gene transcription. Using liq. chromatog.-mass spectrometry (LC-MS), we firstly demonstrate that a peripheral injection of bazedoxifene can enter the brain. Secondly, we show that an acute i.p. injection of bazedoxifene can rescue ovariectomy-induced spatial memory deficits. And finally, using the ERE-luciferase reporter mouse, we show in vivo that bazedoxifene can activate the ERE in the brain. The evidence shown here suggest bazedoxifene could be a viable cognitive enhancer with promising clin. applicability.
- 537Wakeling, A. E.; Dukes, M.; Bowler, J. A Potent Specific Pure Antiestrogen with Clinical Potential. Cancer Res. 1991, 51 (15), 3867– 3873[PubMed], [CAS], Google Scholar544https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXlvFyrtr4%253D&md5=f73c3ea7810ce4780789bc69096f43eaA potent specific pure antiestrogen with clinical potentialWakeling, Alan E.; Dukes, Michael; Bowler, JeanCancer Research (1991), 51 (15), 3867-73CODEN: CNREA8; ISSN:0008-5472.Previous studies from this lab. have described a series of 7α-alkylamide analogs of estradiol with pure antiestrogenic activity, exemplified by ICI 164,384. A new compd., 7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17β-diol (ICI 182,780) has now been identified which has significantly increased antiestrogenic potency and retains pure estrogen antagonist activity. The antiuterotropic potency of ICI 182,780 in the immature rat was more than 10-fold greater than that of ICI 164,384 (50% EDs of 0.06 and 0.9 mg/kg, resp.). This order of magnitude increase of in vivo potency was also reflected, in part, by intrinsic activity at the estrogen receptor. The relative binding affinities of ICI 182,780 and ICI 164,384 were 0.89 and 0.19, resp., compared with that of estradiol (1.0). Similarly, the in vitro growth-inhibitory potency of ICI 182,780 exceeded that of ICI 164,384 in MCF-7 human breast cancer cells, where 50% inhibitory concns. of 0.29 and 1.3 nM, resp., were recorded. ICI 182,780 was a more effective inhibitor of MCF-7 growth than 4'-hydroxytamoxifen, producing an 80% redn. of cell no. under conditions where 4'-hydroxytamoxifen achieved a max. of 50% inhibition. This increased efficacy was reflected by a greater redn. of the proportion of cells engaged in DNA synthesis in ICI 182,780-treated cell cultures compared with tamoxifen-treated cells. Sustained antiestrogenic effects, following a single parental dose of ICI 182,780 in oil suspension, were apparent in both rats and pigtail monkeys. In vivo, antitumor activity of ICI 182,780 was demonstrated with xenografts of MCF-7 and Br10 human breast cancers in nude mice. A single injection of ICI 182,780 provided antitumor efficacy equiv. to that of daily tamoxifen treatment for at least 4 wk. The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer.
- 538Garner, F.; Shomali, M.; Paquin, D.; Lyttle, C. R.; Hattersley, G. RAD1901: A Novel, Orally Bioavailable Selective Estrogen Receptor Degrader That Demonstrates Antitumor Activity in Breast Cancer Xenograft Models. Anti-Cancer Drugs 2015, 26 (9), 948– 956, DOI: 10.1097/CAD.0000000000000271[Crossref], [PubMed], [CAS], Google Scholar545https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlGkt7vK&md5=acb860904a82a83b03b97b40420b64e1RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft modelsGarner, Fiona; Shomali, Maysoun; Paquin, Dotty; Lyttle, C. Richard; Hattersley, GaryAnti-Cancer Drugs (2015), 26 (9), 948-956CODEN: ANTDEV; ISSN:0959-4973. (Lippincott Williams & Wilkins)Agents that inhibit estrogen prodn., such as aromatase inhibitors or those that directly block estrogen receptor (ER) activity, such as selective estrogen receptor modulators and selective estrogen receptor degraders, are routinely used in the treatment of ER-pos. breast cancers. However, although initial treatment with these agents is often successful, many women eventually relapse with drug-resistant breast cancers. To overcome some of the challenges assocd. with current endocrine therapies and to combat the development of resistance, there is a need for more durable and more effective ER-targeted therapies. Here we describe and characterize a novel, orally bioavailable small-mol. selective estrogen receptor degrader, RAD1901, and evaluate its therapeutic potential for the treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-pos. breast cancer cell proliferation. Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models. In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-pos. breast cancer that has metastasized to the brain. Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues. RAD1901 is currently under clin. study in postmenopausal women with ER-pos. advanced breast cancer.
- 539Conlan, M. G.; de Vries, E. F. J.; Glaudemans, A.; Wang, Y.; Troy, S. Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women. Eur. J. Drug Metab. Pharmacokinet. 2020, 45 (5), 675– 689, DOI: 10.1007/s13318-020-00635-3[Crossref], [PubMed], [CAS], Google Scholar546https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlOisrzN&md5=96e466c99d3ca7bc506d5ff27e834f5bPharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal WomenConlan, Maureen G.; de Vries, Erik F. J.; Glaudemans, Awjm; Wang, Yamei; Troy, StevenEuropean Journal of Drug Metabolism and Pharmacokinetics (2020), 45 (5), 675-689CODEN: EJDPD2; ISSN:0378-7966. (Springer France)Abstr.: Background and Objectives: Advanced estrogen receptor-pos. (ER+) breast cancer is currently treated with endocrine therapy. Elacestrant is a novel, nonsteroidal, selective estrogen receptor degrader with complex dose-related ER agonist/antagonist activity that is being developed as a treatment option for ER+ breast cancer. Methods: Two first-in-human phase 1 studies of elacestrant in healthy postmenopausal women (Study 001/Study 004) were conducted to det. its pharmacokinetic and pharmacodynamic profile as well as its safety and max. tolerated dose. Results: In total, 140 postmenopausal subjects received at least one dose of study drug (114 received elacestrant and 26 received placebo). Single-ascending dose and multiple-ascending dose assessments showed that doses up to 1000 mg daily were safe and well tolerated, and the max. tolerated dose was not reached. Oral administration of elacestrant had an abs. bioavailability of 10% and a mean half-life ranging from 27 to 47 h, reaching steady state after 5-6 days. Mean occupancy of the ER in the uterus after seven daily doses was 83% for 200 mg and 92% for 500 mg daily. The median ratio of elacestrant concns. in the cerebral spinal fluid vs. plasma was 0.126% (500 mg dose) and 0.205% (200 mg dose). Most adverse events were related to the upper gastrointestinal tract.